rs1800562

chr6-26092913-G-A

• Frequency:
  • Genomes: 𝑓 0.037 (151 hom., cov: 31)
  • Exomes 𝑓: 0.033 (244 hom.)
• Consequence: HFE NM_000410 missense
• Clinical Significance: Conflicting interpretations of pathogenicity; other; risk factor criteria provided, conflicting interpretations P:34 U:1 B:1 O:6
• Conservation: PhyloP100: 5.23

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL [when 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 [Conflicting_interpretations_of_pathogenicity, other, risk_factor]. Clinvar id is 9. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=30, risk_factor=1, Pathogenic_low_penetrance=1, Uncertain_significance=1, other=1}. 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. gnomad allele frequency = 0.0373 (5679/152164) while in subpopulation NFE AF= 0.0647 (4398/68018). AF 95% confidence interval is 0.0631. There are 151 homozygotes in gnomad. There are 2539 alleles in male gnomad 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
• BS2: High Homozygotes in GnomAd at 151 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HFE	NM_000410.4	c.845G>A	p.Cys282Tyr	missense_variant	4/6	ENST00000357618.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HFE	ENST00000357618.10	c.845G>A	p.Cys282Tyr	missense_variant	4/6	1	NM_000410.4	P3

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 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

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: Conflicting interpretations of pathogenicity; other; risk factor

Submissions summary: Pathogenic:34Uncertain:1Benign:1Other:6

Revision: criteria provided, conflicting interpretations

LINK:

Submissions by phenotype

Hemochromatosis type 1 Pathogenic:18Benign:1Other:1

Pathogenic, no assertion criteria provided	research	Genomics And Bioinformatics Analysis Resource, Columbia University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Jul 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 02, 2022	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. -
Benign, no assertion criteria provided	literature only	OMIM	Jan 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no assertion provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 20, 2022	The variant c.845G>A has previously been reported as the most common variant, with approximately 80-90% of reported cases with hemochromatosis type 1 in homozygous or compound heterozygous state [PMID: 20301613]. The variant co-segregated with the disease in multiple affected family members [PMID: 32153640; 11478530]. The c.845G>A variant has been deposited in ClinVar [ClinVar ID: 9] as Pathogenic by multiple submitters. The c.845G>A variant is observed in 19516 alleles (3.30% minor allele frequency with 536 homozygotes) in population databases (gnomAD v2.1.1 andv3.1.2, TOPMed Freeze 8) with ~5.75% minor allele frequency in individuals of European (non-Finnish) ancestry. The c.845G>A variant is located in exon 4 of this 6-exon gene and is predicted to replace a conserved cysteine amino acid with tyrosine at position 282 in the alpha-3 domain of the encoded protein [PMID: 9162021]. Multiple functional studies have demonstrated that this variant results in an abolished interaction with β2-microglobulin, impaired intracellular trafficking, and accelerated degradation of HFE protein [PMID:11040194, 23953397]. In silico predictions are in favor of damaging effect for p.(Cys282Tyr) variant [(CADD v1.6 = 25.5,REVEL = 0.872)]. Based on available evidence, this c.845G>A p.(Cys282Tyr) variant identified in HFE is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 14, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Sep 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 26, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 05, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jun 24, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 12, 2022	This variant was identified as homozygous._x000D_ Criteria applied: PS3, PM3_STR, PP3, PP4 -

not provided Pathogenic:8Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 01, 2021	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2020	Common pathogenic variant associated with hereditary hemochromatosis (Cezard et al., 2014; Feder et al., 1996); 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 (Waheed et al., 1997); Observed in 9,544/282,608 global alleles (3.4%), including 267 homozygous control individuals, in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9356458, 23792061, 32153640, 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, 21243428, 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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	Criteria applied: PS3:Strong, PS4:Strong, PP4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -

Hereditary hemochromatosis Pathogenic:2Other:2

Pathogenic, low penetrance, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2022	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HFE protein function. 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). -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	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. -
not provided, no assertion provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	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/. -
not provided, no assertion provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -

HFE-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Jun 07, 2022

PS3, PM3_Very Strong, PP3 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Region Ostergotland

Apr 15, 2021

PS3, PP5, PS4, PM3 -

Abdominal pain;C0030193:Pain;C0031117:Peripheral neuropathy;C0233514:Atypical behavior;C0497552:Abnormality of the nervous system;C4023819:Abnormality of the male genitalia;C4025831:Abnormal peripheral nervous system morphology Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

May 11, 2018

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Vantari Genetics

Dec 01, 2015

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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. -

Porphyrinuria;C0349506:Cutaneous photosensitivity Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 12, 2014

- -

Hemochromatosis type 2 Other:1

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2020

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

not provided, no assertion provided

phenotyping only

GenomeConnect, ClinGen

-

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

26

Dann

Uncertain

0.99

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

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A

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

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;