ClinVar Miner

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

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Total submissions: 30
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000000019 SCV000151394 pathogenic Hemochromatosis type 1 2015-09-14 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000000019 SCV000206975 pathogenic Hemochromatosis type 1 2015-11-26 criteria provided, single submitter clinical testing
Invitae RCV000308358 SCV000219175 pathogenic Hereditary hemochromatosis 2020-10-31 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).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844709 SCV000221190 risk factor Hemochromatosis type 2 2020-03-04 criteria provided, single submitter 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.
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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000178096 SCV000230091 other not provided 2018-05-31 criteria provided, single submitter clinical testing
Vantari Genetics RCV000210820 SCV000267038 pathogenic Hereditary cancer-predisposing syndrome 2015-12-01 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.
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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414811 SCV000493004 uncertain significance Cutaneous photosensitivity; Porphyrinuria 2014-04-12 criteria provided, single submitter clinical testing
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.
Mendelics RCV000000019 SCV001137062 pathogenic Hemochromatosis type 1 2019-05-28 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000000019 SCV001194044 pathogenic Hemochromatosis type 1 2019-12-09 criteria provided, single submitter 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000178096 SCV001246053 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000000019 SCV001251531 pathogenic Hemochromatosis type 1 criteria provided, single submitter 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).
Institute of Human Genetics, University of Leipzig Medical Center RCV001262214 SCV001440001 pathogenic Alzheimer disease 2019-01-01 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV001270034 SCV001448752 pathogenic Abnormality of the nervous system; Behavioral abnormality; Abdominal pain; Abnormal peripheral nervous system morphology; Abnormality of the male genitalia; Pain; Peripheral neuropathy 2018-05-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000019 SCV001519562 pathogenic Hemochromatosis type 1 2021-02-23 criteria provided, single submitter 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.
Baylor Genetics RCV000000019 SCV001523198 pathogenic Hemochromatosis type 1 2020-07-29 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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
GeneReviews RCV000000019 SCV000245793 pathogenic Hemochromatosis type 1 2015-09-17 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV001248830 SCV000607202 not provided Bronze diabetes no assertion provided phenotyping only Variant interpretted as Pathogenic and , most recently, reported on 03-14-2019 by Lab or GTR ID 500068. 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000000019 SCV000883106 pathogenic Hemochromatosis type 1 2019-07-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000178096 SCV001549492 pathogenic not provided no assertion criteria provided 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.

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