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rs1800562

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 9P and 6B. PP3PP5_Very_StrongBP4BS1_SupportingBS2

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

Scores

9
4
3

Clinical Significance

Pathogenic/Pathogenic, low penetrance; other; risk factor criteria provided, multiple submitters, no conflicts P:39U:1B:1O:6

Conservation

PhyloP100: 5.23
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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 [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: {Pathogenic=34, risk_factor=1, Benign=1, Pathogenic_low_penetrance=1, Uncertain_significance=1, not_provided=4, 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 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. 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
HFENM_000410.4 linkuse as main transcriptc.845G>A p.Cys282Tyr missense_variant 4/6 ENST00000357618.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HFEENST00000357618.10 linkuse as main transcriptc.845G>A p.Cys282Tyr missense_variant 4/61 NM_000410.4 P3Q30201-1

Frequencies

GnomAD3 genomes
AF:
0.0373
AC:
5679
AN:
152164
Hom.:
151
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:39Uncertain:1Benign:1Other:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hemochromatosis type 1 Pathogenic:22Benign:1Other:1
Pathogenic, no assertion criteria providedresearchGenomics And Bioinformatics Analysis Resource, Columbia University-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMay 29, 2023- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genomics Laboratory, Washington University in St. LouisSep 12, 2023The 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. -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsNov 26, 2015- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 23, 2021Variant 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, no assertion criteria providedclinical testingClinical Genetics Laboratory, University Hospital Schleswig-HolsteinSep 23, 2021- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalNov 05, 2023This 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. -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterMay 15, 2023- -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease CompanyJun 24, 2019- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityMar 30, 2016The 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 submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneJul 25, 2019- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 09, 2019NM_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 submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGenomic Medicine Lab, University of California San FranciscoJul 21, 2020- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaFeb 02, 2022The 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. -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 14, 2015- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterresearchUNC 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, no assertion criteria providedresearchdeCODE genetics, AmgenJul 21, 2023The 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. -
Benign, flagged submissionliterature onlyOMIMJan 01, 2009- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterApr 12, 2022This variant was identified as homozygous._x000D_ Criteria applied: PS3, PM3_STR, PP3, PP4 -
Pathogenic, criteria provided, single submitterclinical testingClinical Genomics Program, Stanford MedicineJun 01, 2021• 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] -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJun 30, 2022- -
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineJun 05, 2017The 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. -
not provided Pathogenic:8Other:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsMar 08, 2022- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicDec 01, 2021- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 25, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024HFE: PM3:Very Strong, PS3, PM2:Supporting -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 27, 2020Common 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, no assertion criteria providedclinical testingDepartment 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. -
other, criteria provided, single submitterclinical testingEurofins 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 submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenSep 15, 2021- -
Hereditary hemochromatosis Pathogenic:2Other:2
not provided, no classification providedphenotyping onlyGenomeConnect - 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/. -
Pathogenic, criteria provided, single submitterclinical testingDASAJan 05, 2022The 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 classification providedphenotyping onlyGenomeConnect - 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. -
Pathogenic, low penetrance, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This 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 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). -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 27, 2021The 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 submitterclinical testingClinical Genetics Laboratory, Region OstergotlandApr 15, 2021PS3, PP5, PS4, PM3 -
HFE-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJun 07, 2022PS3, PM3_Very Strong, PP3 -
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 submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityMay 11, 2018- -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingVantari GeneticsDec 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 submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021HFE 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. -
HFE-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 11, 2024The 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. -
Porphyrinuria;C0349506:Cutaneous photosensitivity Uncertain:1
Uncertain significance, flagged submissionclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaApr 12, 2014- -
Bronze diabetes Other:1
not provided, no classification providedphenotyping onlyGenomeConnect, 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. -
Juvenile hemochromatosis Other:1
risk factor, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 04, 2020HFE 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. -

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
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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1800562; hg19: chr6-26093141; API