ClinVar Miner

Submissions for variant NM_000410.3(HFE):c.845G>A (p.Cys282Tyr) (rs1800562)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics, RCV000000019 SCV000206975 pathogenic Hemochromatosis type 1 2015-11-26 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414811 SCV000493004 uncertain significance Cutaneous photosensitivity; Porphyrinuria 2014-04-12 criteria provided, single submitter clinical testing
Counsyl RCV000000019 SCV000677906 pathogenic Hemochromatosis type 1 2016-03-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000178096 SCV000230091 other not provided 2018-05-31 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000000019 SCV000883106 likely pathogenic Hemochromatosis type 1 2018-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000178096 SCV000329362 pathogenic not provided 2019-01-21 criteria provided, single submitter clinical testing The C282Y variant in the HFE gene is the most common pathogenic variant associated with hereditary hemochromatosis (Cezard et al., 2014; Feder et al., 1996). The C282Y variant is observed in 7,275/126,464 (5.7%%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The C282Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies have shown that the C282Y results in a protein that does not reach the cell surface and is subject to accelerated degradation (Waheed et al., 1997). We interpret C282Y as a pathogenic variant.
GeneReviews RCV000000019 SCV000245793 pathogenic Hemochromatosis type 1 2015-09-17 no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000000019 SCV000151394 pathogenic Hemochromatosis type 1 2015-09-14 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000308358 SCV000607202 not provided Hereditary hemochromatosis no assertion provided phenotyping only 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.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000000019 SCV000839959 pathogenic Hemochromatosis type 1 2017-06-05 criteria provided, single submitter 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.
Illumina Clinical Services Laboratory,Illumina RCV000000019 SCV000461887 pathogenic Hemochromatosis type 1 2019-04-05 criteria provided, single submitter clinical testing The HFE c.845G>A (p.Cys282Tyr) missense variant is one of the two most common and well-studied pathogenic variants associated with hereditary hemochromatosis (HH), with approximately 80-87% of HH type 1 patients of European origin being homozygous or compound heterozygous for this variant (Feder et al. 1996; Gallego et al. 2015; Press et al. 2016). Disease penetrance for the p.Cys282Tyr 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 (Seckington et al. 2015; Gallego et al. 2015). The p.Cys282Tyr 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). The p.Cys282Tyr variant has a frequency of 5% to 7% in Caucasians (Press et al. 2016) and is reported at a frequency of 0.06407 in the European American population of the Exome Sequencing Project. This allele frequency is high but is consistent with estimates of disease prevalence and reduced penetrance. Based on the collective evidence, the p.Cys282Tyr variant is classified as pathogenic for hereditary hemochromatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000308358 SCV000219175 pathogenic Hereditary hemochromatosis 2019-01-07 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 282 of the HFE protein (p.Cys282Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs1800562, ExAC 5%). 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). 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). For these reasons, this variant has been classified as Pathogenic (low penetrance).
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000000019 SCV000223934 pathogenic Hemochromatosis type 1 2016-03-30 criteria provided, single submitter 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844709 SCV000221190 pathogenic Hemochromatosis type 2 2014-03-19 criteria provided, single submitter clinical testing The p.Cys282Tyr variant in HFE is a well-established pathogenic variant for here ditary hemochromatosis (HH). Although it is considered pathogenic, the penetranc e is significantly reduced. Biochemically, 82% of p.Cys282Tyr homozygotes and 17 % of p.Cys282Tyr/p.His63Asp compound heterozygotes were shown to have elevated t ransferrin saturation (Pederson 2009); however, less than 5% of individuals with biallelic pathogenic HFE variants exhibit clinical symptoms of HH (Beutler 2002 , Gurrin 2009). In summary, this variant meets criteria to be classified as path ogenic for HH in an autosomal recessive pattern but with significantly reduced p enetrance. ACMG/AMP Criteria applied: PS3; PS4; PM3.
OMIM RCV000000019 SCV000020162 pathogenic Hemochromatosis type 1 2009-01-01 no assertion criteria provided literature only
OMIM RCV000000020 SCV000020163 risk factor Porphyria cutanea tarda, susceptibility to 2009-01-01 no assertion criteria provided literature only
OMIM RCV000000021 SCV000020164 risk factor Porphyria variegata, susceptibility to 2009-01-01 no assertion criteria provided literature only
OMIM RCV000000022 SCV000020165 pathogenic Hemochromatosis, juvenile, digenic 2009-01-01 no assertion criteria provided literature only
OMIM RCV000000023 SCV000020166 risk factor Alzheimer disease, susceptibility to 2009-01-01 no assertion criteria provided literature only
OMIM RCV000000024 SCV000020167 association Transferrin serum level quantitative trait locus 2 2009-01-01 no assertion criteria provided literature only
OMIM RCV000000025 SCV000020168 risk factor Microvascular complications of diabetes 7 2009-01-01 no assertion criteria provided literature only
Vantari Genetics RCV000210820 SCV000267038 pathogenic Hereditary cancer-predisposing syndrome 2015-12-01 criteria provided, single submitter clinical testing

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