rs1800562

Variant names:

• chr6-26092913-G-A
• rs1800562
• NM_000410.4:c.845G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-26092913-G-A
• chr6-26092913-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 9P and 2B. PP3 PP5_Very_Strong BP4 BS1_Supporting

The NM_000410.4(HFE):​c.845G>A​(p.Cys282Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.057 in 1,614,134 control chromosomes in the GnomAD database, including 3,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic low penetrance,other,risk factor (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (151 hom., cov: 31)
  • Exomes 𝑓: 0.059 (3248 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Pathogenic/Pathogenic, low penetrance; other; risk factor criteria provided, multiple submitters, no conflicts P:46 U:1 B:1 O:6
• Conservation: PhyloP100: 5.23

Genes affected

HFE (HGNC:4886): (homeostatic iron regulator) The protein encoded by this gene is a membrane protein that is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). It is thought that this protein functions to regulate iron absorption by regulating the interaction of the transferrin receptor with transferrin. The iron storage disorder, hereditary haemochromatosis, is a recessive genetic disorder that results from defects in this gene. [provided by RefSeq, May 2022]

H2BC4 (HGNC:4757): (H2B clustered histone 4) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. The protein has antibacterial and antifungal antimicrobial activity. The main transcript variant of this gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. This transcript variant lacks a polyA tail but instead contains a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Apr 2020]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 6-26092913-G-A is Pathogenic according to our data. Variant chr6-26092913-G-A is described in ClinVar as [Pathogenic_low_penetrance, other, risk_factor]. Clinvar id is 9.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {other=1, risk_factor=1, Pathogenic_low_penetrance=1, Uncertain_significance=1, Pathogenic=40, not_provided=4}. Variant chr6-26092913-G-A is described in Lovd as [Pathogenic]. Variant chr6-26092913-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0073376894). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0373 (5679/152282) while in subpopulation NFE AF= 0.0647 (4398/68010). AF 95% confidence interval is 0.0631. There are 151 homozygotes in gnomad4. There are 2539 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFE	NM_000410.4	c.845G>A	p.Cys282Tyr	missense_variant	Exon 4 of 6	ENST00000357618.10	NP_000401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFE	ENST00000357618.10	c.845G>A	p.Cys282Tyr	missense_variant	Exon 4 of 6	1	NM_000410.4	ENSP00000417404.1

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5679 AN: 152164 Hom.: 151 Cov.: 31

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0356

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0647

Gnomad OTH AF: 0.0278

GnomAD3 exomes AF: 0.0332 AC: 8344 AN: 251236 Hom.: 244 AF XY: 0.0323 AC XY: 4391 AN XY: 135842

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00222

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.0574

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0590 AC: 86298 AN: 1461852 Hom.: 3248 Cov.: 34 AF XY: 0.0568 AC XY: 41284 AN XY: 727228

Gnomad4 AFR exome AF: 0.00989

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00214

Gnomad4 FIN exome AF: 0.0370

Gnomad4 NFE exome AF: 0.0714

Gnomad4 OTH exome AF: 0.0571

GnomAD4 genome AF: 0.0373 AC: 5679 AN: 152282 Hom.: 151 Cov.: 31 AF XY: 0.0341 AC XY: 2539 AN XY: 74446

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0356

Gnomad4 NFE AF: 0.0647

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0527 Hom.: 547

Bravo AF: 0.0348

TwinsUK AF: 0.0690 AC: 256

ALSPAC AF: 0.0794 AC: 306

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.0641 AC: 551

ExAC AF: 0.0324 AC: 3937

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0569

EpiControl AF: 0.0502

ClinVar

Significance: Pathogenic/Pathogenic, low penetrance; other; risk factor

Submissions summary: Pathogenic:46 Uncertain:1 Benign:1 Other:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 1 Pathogenic:28 Benign:1 Other:1

Jun 01, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

• The p.Cys282Tyr variant in the HFE gene has been identified in the homozygous state in approximately 60- 90% of individuals of European ancestry with HFE hemochromatosis, and in the compound heterozygous state with p.His63Asp in approximately 3-8% of individuals of European ancestry with HFE hemochromatosis (Barton and Edwards, 2018). • The p.Cys282Tyr variant is associated with a high penetrance for biochemical evidence of iron overload, but with a low penetrance for clinical manifestations of iron overload with studies reporting evidence of clinical disease present in as low as 2% and as high as 33% of p.Cys282Tyr homozygotes (Beutler et al., 2002; Whitlock et al., 2006). • Individuals heterozygous for the p.Cys282Tyr variant may demonstrate evidence of biochemical disease, including mildly elevated serum transferrin-iron saturation and serum ferritin concentration, but do not develop clinical manifestations of disease (Allen et al., 2008; Pedersen and Milman, 2009). • This variant has been identified in 7,435/128,950 European (non-Finnish) chromosomes (9,544/282,608 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although the p.Cys282Tyr variant is seen at a frequency greater than 5% in the general population, this variant is recognized as a common low-penetrant variant that is an exception to ACMG/AMP classification guidelines (Ghosh et al., 2018). • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Cys282Tyr variant as pathogenic for autosomal recessive HFE hemochromatosis based on the information above. [ACMG evidence codes used: PS4; PP3] -

Jun 05, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.845G>A (p.Cys282Tyr) variant in the HFE gene in the homozygous state has been reported as a common cause of hereditary hemochromatosis with high penetrance of biochemically defined iron overload but low penetrance of clinically defined iron overload [OMIM:613609.0001; PMID 8896549, 10381492, 18199861]. This variant has been detected at high frequency in the ExAC population database (up to 5% in Europeans) (http://exac.broadinstitute.org/variant/6-26093141-G-A). Cysteine at amino acid position 282 of the HFE protein is highly conserved in mammals and computer-based algorithms predict this p.Cys282Tyr change to be deleterious. This variant is classified as pathogenic.<BR>Apparent homozygosity of this variant may be caused by the presence of the mutant allele on both alleles of this individual, or the presence of a mutant allele on one allele and an exonic deletion on the opposite allele. Copy number variant (CNV) analysis or segregation analysis is necessary to assess the apparent homozygosity status of this variant. -

Feb 23, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HFE c.845G>A (p.Cys282Tyr) results in a non-conservative amino acid change located in the Immunoglobulin C1-set domain (IPR003597) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.033 in 251236 control chromosomes in the gnomAD database, including 244 homozygotes. c.845G>A has been reported in the literature as the most common mutation found in individuals with Hemochromatosis Type 1, being identified as homozygous or compound heterozygous with another pathogenic variant in approximately 80-90% of reported cases, most frequently in individuals of European ancestry (e.g. Feder_1996, LeGac_2004, Beutler_2002, Yonal_2007, vanGemmeren_2015, deTayrac_2015, Zhang_2020). These data indicate that the variant is likely to be associated with disease, however the variant appears to have significantly reduced penetrance, as the majority of homozygous or compound heterozygous individuals with this variant do not exhibit clinical symptoms of the disorder despite some cases having elevated serum ferritin and transferrin saturation levels (e.g. Feder_1996, Beutler_2002, Yonal_2007). The mechanisms behind the variable expressivity of this variant are not known, but it has been proposed that other genetic variants could modify the phenotype exhibited by individuals who are homozygous for this variant (e.g. LeGac_2004, deTayrac_2015). In-vitro experimental evidence suggests that the Cys282Tyr-mutant protein has impaired intracellular trafficking and accelerated degradation compared to wild-type HFE (e.g. Waheed_1997) and that cells expressing the variant have altered expression of genes involved in sphingolipid metabolism (e.g. Ali-Rahmani_2011). In addition, an in-vivo study reported a loss of CD8+ T-cell tolerance to HFE in transgenic mice expressing the C282Y variant (e.g. Boucherma_2012) . Seventeen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Sixteen of these laboratories cited the variant as pathogenic/likely pathogenic or as a risk factor for disease. Based on the evidence outlined above, the variant was classified as pathogenic with low penetrance for developing Hemochromatosis. -

Nov 26, 2015

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Sep 14, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Mar 30, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.845G>A (p.Cys282Tyr) missense variant is widely recognized as one of the two most common disease-causing variants in the HFE gene. Cys282Tyr homozygotes account for 80-85% of typical patients with Hereditary Hemochromatosis (HH). However, the majority of individuals who are homozygous for this variant do not develop the disease (GeneReviews, Kowdley et al., 2012; Ramrakhiani and Bacon, 1998; and Morrison et al., 2003). In summary, this variant c.845G>A (p.Cys282Tyr) meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. -

Sep 23, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Jul 21, 2020

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2019

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000410.3(HFE):c.845G>A(C282Y) is classified as pathogenic in the context of HFE-associated hereditary hemochromatosis. Please note that clinical symptoms are uncommon in C282Y homozygotes. Sources cited for classification include the following: PMID 9162021, 9356458, 8931958, 9341868, 9462220 and 11812557. Classification of NM_000410.3(HFE):c.845G>A(C282Y) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 21, 2023

deCODE genetics, Amgen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant NM_000410.4:c.845G>A (chr6:26092913) in HFE was detected in 7331 heterozygotes and 264 homozygotes out of 58K WGS Icelanders (MAF= 6,775%). Following imputation in a set of 166K Icelanders (710 imputed homozygotes) we observed an association with hemochromatosis under a recessive model using 2403 cases and 240747 controls (OR= 50.27, P= 2.69e-212). This variant has been reported multiple times in ClinVar as pathogenic. Based on ACMG criteria (PS3, PS4, PP1, PP4, PP5) this variant classifies as pathogenic. -

Sep 25, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PM3_STR,PP3,PP4 -

Jun 30, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.845G>A(p.Cys282Tyr) in HFE gene has been reported in homozygous state in multiple individuals affected with hemochromatosis (Porto G et. al., 2016; Gallego et. al., 2015). Experimental studies have shown that this missense change disrupts a disulfide bond in the α3 domain of the HFE protein and impairs interaction of HFE with beta2-microglobulin, resulting in a block in intracellular transport and loss of cell surface expression of the Cys282Tyr variant protein (Waheed et. al., 1997). The observed variant has allele frequency of 3.3% in gnomAD exomes database. This variant has been submitted to the ClinVar database as risk factor / Uncertain Significance / Pathogenic (multiple submissions). The reference amino acid change p.Cys282Tyr in HFE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 282 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Sep 12, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HFE c.845G>A (p.Cys282Tyr) variant has been reported in the homozygous or compound heterozygous state in many individuals affected with hereditary hemochromatosis and is considered the most common cause of hereditary hemochromatosis (Barton JC and Edwards CQ, PMID: 20301613). Studies show penetrance rates of severe iron overload to be as high as 35% and severe liver disease in 9–24% among male p.Cys282Tyr homozygotes (Grosse SD et al., PMID: 28771247). This variant has been reported in the ClinVar database as a germline pathogenic variant by many submitters. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HFE function. In support of these predictions, a homozygous mouse model showed postnatal iron loading and in vitro functional studies have shown that the variant causes reduced function (Ali-Rahmani F et al., PMID: 21243428; Boucherma R et al., PMID: 22531912; Levy JE et al., PMID: 10381492). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic with reduced penetrance. -

Jan 01, 2009

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 25, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2019

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_VeryStrong+PS3 -

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with haemochromatosis (MIM#235200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. The highest biochemical and clinical penetrance has been reported in p.(Cys282Tyr) homozygotes (PMID: 20301613). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0252 - This variant is homozygous. (I) 0307 - Variant is present in gnomAD at a frequency >=0.05 (v2: 8992 heterozygotes, 276 homozygotes). (SB) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated IgC MHC I alpha3 functional domain (NCBI). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has previously been described as pathogenic in multiple patients with haemochromatosis (ClinVar; PMIDs: 37260121, 9162021, 19159930); either in a homozygous state or in trans with NP_000401.1(HFE):p.(His63Asp). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis using transfected cell lines showed defects in HFE protein intracellular transport and cell surface expression (PMID: 9162021). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The HFE c.845G>A (p.C282Y) variant is a pathogenic variant observed in 3.4% of the human population (gnomAD). Individuals that are homozygous for the p.C282Y variant have a greater risk of developing iron overload compared to individuals with compound heterozygous variants (i.e. c.845G>A p.C282Y and c.187C>G p.H63D in trans) (PMID: 20301613). -

Jun 14, 2024

Institute of Human Genetics, Heidelberg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Feb 02, 2022

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HFE c.845G>A (p.Cys282Tyr) missense variant results in the substitution of cysteine at amino acid position 282 to tyrosine. This variant is one of the two most common and well-studied pathogenic variants associated with HFE hemochromatosis. Approximately 60-90% of individuals of European ancestry with HFE hemochromatosis are homozygous for the variant and between 3-8% of individuals are compound heterozygous (Feder et al. 1996; Morrison et al. 2003; Gallego et al. 2015; Press et al. 2016; Barton and Edwards 2018). Disease penetrance for c.845G>A variant carriers is variable (Beutler et al. 2002; Pedersen et al. 2009; Gurrin et al. 2009), with homozygotes being at a greater risk for iron overload than compound heterozygotes (Gallego et al. 2015; Barton and Edwards 2018). The c.845G>A variant affects HFE protein activity by preventing the formation of a disulfide bridge in the alpha-3 domain, which impairs the beta-2-microglobulin interaction and prevents the protein from reaching the cell surface (Feder et al. 1997; Barton and Edwards 2018). The c.845G>A variant has a frequency of 5-7% in Caucasians (Press et al. 2016) and is reported at a frequency of 0.064660 in the European (non-Finnish) population (including 137 homozygotes) of the Genome Aggregation Database (version 3.1.2). This allele frequency is high but is consistent with estimates of disease prevalence. Based on the available evidence, the c.845G>A (p.Cys282Tyr) variant is classified as pathogenic for HFE hemochromatosis but is noted to have reduced penetrance. -

Jun 17, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PS3, PS4, PM3, PP1_M, PP5; Variant was found in compound heterozygous state with NM_000410.4:c.187C>G. -

May 15, 2023

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Nov 05, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in HFE is predicted to replace cysteine with tyrosine at codon 282, p.(Cys282Tyr). The cysteine residue is highly conserved (100 vertebrates, UCSC), and alters a critical cysteine residue involved in a disulfide bond in the Ig-like C2 type domain and prevents HFE protein presentation (PMID: 20301613). There is a large physicochemical difference between cysteine and tyrosine. The highest population minor allele frequency in the population database gnomAD v2.1 is 5.6% (7,345/128,950 alleles, 243 homozygotes) in the European non-Finnish population. This variant is reported as the common cause of HFE-related haemochromatosis. It has been reported in multiple individuals with haemochromatosis who were either homozygous or compound heterozygous for the variant (PMID: 19159930, 32153640, 11903354). The variant has been reported to segregate with haemochromatosis in multiple affected individuals from unrelated families (PMID: 10575540, 27518069). In vitro functional assays with limited validation showed a significant impairment to protein trafficking and accelerated protein degradation indicating that this variant impacts protein function (PMID: 9162021, 9356458). A transgenic mouse model for the variant showed an increased predisposition to iron loading (PMID: 10381492). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.872). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: BS1, PM3_VeryStrong, PM1, PP1_Strong, PP3, PS3_Moderate. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:9 Other:1

May 31, 2018

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Jul 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Common pathogenic variant associated with hereditary hemochromatosis (PMID: 23953397, 8696333); Published functional studies demonstrate a damaging effect as C282Y results in a protein that does not reach the cell surface and is subject to accelerated degradation (PMID: 21243428, 9356458); This variant is associated with the following publications: (PMID: 9356458, 23792061, 32153640, 34490613, 26474245, 29969830, 23953397, 19084217, 19159930, 19271219, 20117027, 19176287, 24604426, 12707220, 22693327, 19258483, 20031541, 20031565, 9836708, 23121079, 20640879, 20946107, 22531912, 23178241, 20099304, 22611049, 20669231, 19820015, 21785125, 23222517, 21514009, 19429178, 22209421, 23281741, 20560808, 17450498, 8696333, 26501199, 27661980, 27659401, 26365338, 25916738, 27153395, 25767899, 11903355, 29555771, 30291871, 30374069, 15254010, 31019283, 31028937, 31640930, 29301508, 25287020, 32189932, 31447099, 30145563, 31980526, 26893171, 32228506, 34426522, 9630070, 9674544, 11336458, 11478530, 11531973, 11976822, 9382962, 10520044, 32641076, 11565552, 9858243, 19912313, 10792295, 11181289, 10090890, 11500063, 11189980, 32874917, 37937776, 27816425, 37443404, 38195192, 28399358, 29145899, 35499102, 27784128, 21243428) -

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Sep 20, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Mar 08, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Oct 25, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HFE p.Cys282Tyr variant is a common variant known to cause hereditary hemochromatosis; over 80% of hereditary hemochromatosis patients are homozygous for the p.C282Y variant (Feder_1996_PMID:8696333; Morrison_2003_PMID:12693884). The variant was identified in dbSNP (ID: rs1800562), in ClinVar (classified as pathogenic 13 times, likely pathogenic once and as a VUS once) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 9544 of 282608 chromosomes (276 homozygous) at a frequency of 0.033771 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 7435 of 128950 chromosomes (freq: 0.05766), Other in 281 of 7224 chromosomes (freq: 0.0389), European (Finnish) in 879 of 25108 chromosomes (freq: 0.03501), Latino in 494 of 35430 chromosomes (freq: 0.01394), Ashkenazi Jewish in 124 of 10366 chromosomes (freq: 0.01196), African in 260 of 24962 chromosomes (freq: 0.01042), South Asian in 68 of 30616 chromosomes (freq: 0.002221), and East Asian in 3 of 19952 chromosomes (freq: 0.00015). The p.Cys282 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Functional studies of the p.C282Y variant have demonstrated abnormal protein interaction, expression, processing and localization (Feder_1997_PMID:9162021; Waheed_1997_PMID:9356458). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HFE: PM3:Very Strong, PS3, PM2:Supporting -

Dec 12, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hemochromatosis Pathogenic:2 Other:2

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.845G>A;p.(Cys282Tyr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 9; OMIM: 613609.0001; PMID: 20301613; 27659401; 26365338; 19084217; 11040194; 23953397; 26365338) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11040194; 23953397; 9162021; 9356458) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Immunoglobulin C1-set domain) - PM1. The p.(Cys282Tyr) was detected in trans with a pathogenic variant (PMID: 15507752; 17384005; 26244503; 25850353; 25277871; 24401005; 23953397; 32153640; 11478530; 26365338) - PM3_very strong The variant co-segregated with disease in multiple affected family members (PMID: 32153640; 11478530) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic, low penetrance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 282 of the HFE protein (p.Cys282Tyr). This variant is present in population databases (rs1800562, gnomAD 6%), and has an allele count higher than expected for a pathogenic variant. This is a common, low penetrance variant that is known to contribute to hemochromatosis when homozygous or present with a second pathogenic allele in HFE. As many as 90% of individuals of European descent who are affected with hemochromatosis are homozygous for this variant (PMID: 16132052, 26153218, 26365338). ClinVar contains an entry for this variant (Variation ID: 9). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HFE protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change disrupts a disulfide bond in the α3 domain of the HFE protein and impairs interaction of HFE with beta2-microglobulin, resulting in a block in intracellular transport and loss of cell surface expression of the Cys282Tyr variant protein (PMID: 9162021, 9356458). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the HFE gene, it has been classified as Pathogenic (low penetrance). -

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 11/20/2019 by Illumina and 6/19/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

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GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 05-24-2022 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

HFE-related disorder Pathogenic:2

Jun 07, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM3_Very Strong, PP3 -

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HFE c.845G>A variant is predicted to result in the amino acid substitution p.Cys282Tyr. In patients with transferrin-iron saturation higher than 45%, presence of the c.845G>A (p.Cys282Tyr) variant is useful in confirmation of hereditary hemochromatosis diagnosis as individuals homozygous for the variant represent 80% of cases (Bacon et al. 2011. PubMed ID: 21452290; Alexander and Kowdley. 2009. PubMed ID: 19444013; Kowdley et al. 2012. PubMed ID: 22395570). The c.845G>A (p.Cys282Tyr) variant is incompletely penetrant with ~35% of individuals homozygous for the variant having normal ferritin levels (Bacon et al. 2011. PubMed ID: 21452290). This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1

Sep 27, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.845G>A (p.C282Y) alteration is located in coding exon 4 of the HFE gene. This alteration results from a G to A substitution at nucleotide position 845, causing the cysteine (C) at amino acid position 282 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of 3.38% (9544/282608) total alleles studied. The highest observed frequency was 5.77% (7435/128950) of European (non-Finnish) alleles. This alteration is the most common cause of hereditary hemochromatosis (Allen, 2008). In homozygous individuals, up to 50% may develop iron overload, with 10-33% developing hemochromatosis-associated morbidity (EASL, 2010). Men appear to have a higher risk for disease development than women. In homozygous men, 84% display elevated transferrin-iron saturation and 88% have elevated serum ferritin concentration. In comparison, fewer homozygous women have elevated transferrin-iron saturation and serum ferritin concentration (73% and 57%, respectively). However, when p.C282Y is compound heterozygous with another pathogenic alteration, disease penetrance is significantly lower (Adams, 1997). This amino acid position is highly conserved in available vertebrate species. Functional studies have shown that this alteration leads to impaired intracellular transport of the protein and degradation before reaching the cell surface (Feder, 1997; Waheed, 1997). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Cardiomyopathy Pathogenic:1

Apr 15, 2021

Clinical Genetics Laboratory, Region Ostergotland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP5, PS4, PM3 -

Abdominal pain;C0004941:Atypical behavior;C0030193:Pain;C0031117:Peripheral neuropathy;C0497552:Abnormality of the nervous system;C4023819:Abnormality of the male genitalia;C4025831:Abnormal peripheral nervous system morphology Pathogenic:1

May 11, 2018

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Variegate porphyria;C0268323:Familial porphyria cutanea tarda;C1863052:Alzheimer disease type 1;C2673520:Microvascular complications of diabetes, susceptibility to, 7;C3280096:TRANSFERRIN SERUM LEVEL QUANTITATIVE TRAIT LOCUS 2;C3469186:Hemochromatosis type 1 Pathogenic:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HFE NM_000410.3 exon 4 p.Cys282Tyr (c.845G>A): This variant has been reported in the literature in the homozygous or compound heterozygous state in many individuals with hereditary hemochromatosis (HH) (Allen 2008 PMID:18199861, Pederson 2009 PMID:19159930, Cezard 2014 PMID:23953397, Gallego 2015 PMID:26365338) and is reported to be the most common cause of HH (Le Gac 2005 PMID:16132052, Gallego 2015 PMID:26365338, Porto 2016 PMID:26153218). This variant is present in 3.3% (9544/282608) of total alleles in the Genome Aggregation Database, including 276 homozygotes (https://gnomad.broadinstitute.org/variant/6-26093141-G-A). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:9). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, an in vivo mouse study showed postnatal iron loading in mice homozygous for this variant (Levy 1999 PMID:10381492), and in vitro functional studies have shown that the mutant protein is retained in the ER and is unable to interact with beta2-microglobulin (Feder 1997 PMID:9162021, Waheed 1997 PMID:9356458). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 01, 2015

Vantari Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Porphyrinuria;C0349506:Cutaneous photosensitivity Uncertain:1

Apr 12, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

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Juvenile hemochromatosis Other:1

Mar 04, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: risk factor

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HFE c.845G>A (p.Cys282Tyr) has been associated with increased risk for hemochromatosis. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (5.7%, Genome Aggregation Database (gnomAD); rs1800562) and is present in ClinVar (ID: 9). A large meta-analysis has reported an odds ratio of 1.2 [95% CI 0.8-1.6] for developing liver disease in heterozygous carriers (Ellervik 2007). In vitro and in vivo functional studies provide some evidence that this variant may impact protein function (Ali-Rahmani 2011, Boucherma 2012). In summary, this variant is uncertain risk allele for hemochromatosis in heterozygous state. HFE c.845G>A (p.Cys282Tyr) has been associated with increased risk for hemochromatosis. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (5.7%, Genome Aggregation Database (gnomAD); rs1800562) and is present in ClinVar (ID: 9). A large meta-analysis has reported an odds ratio of 3.9 [95% CI 1.9-8.1] for developing liver disease in homozygous carriers (Ellervik 2007). In vitro and in vivo functional studies provide some evidence that this variant may impact protein function (Ali-Rahmani 2011, Boucherma 2012). In summary, this variant is established risk allele for hemochromatosis in homozygous state. -

Bronze diabetes Other:1

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant identified in multiple participants and classified as Pathogenic. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;.;.;.;T;T;.;.;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0073	T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;.;.;.;H;.;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-8.9	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;D;D;P;D;.
Vest4		0.82
MPC		1.1
ClinPred		0.090	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800562; hg19: chr6-26093141;