ClinVar Miner

Submissions for variant NM_000410.3(HFE):c.187C>G (p.His63Asp) (rs1799945)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844708 SCV000198337 uncertain significance not specified 2020-03-05 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Blueprint Genetics RCV000000026 SCV000206973 pathogenic Hemochromatosis type 1 2015-11-26 criteria provided, single submitter clinical testing
Invitae RCV000394716 SCV000219176 pathogenic Hereditary hemochromatosis 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 63 of the HFE protein (p.His63Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is present in population databases (rs1799945, ExAC 14%). This is a very common, low penetrance variant that is known to contribute to hemochromatosis when present with a second pathogenic allele in HFE. An estimated 1.5% of individuals of European descent who are affected with hemochromatosis are homozygous for this variant (PMID: 11479183), however, penetrance of the homozygous genotype is very low and is associated with variable phenotypes (PMID: 24729993, 11399207, 16132052, 11358905). ClinVar contains an entry for this variant (Variation ID: 10). Experimental studies have shown that while this variant does not affect the localization of the protein on the cell surface or normal HFE interaction with its partner molecules (PMID: 9356458, 9162021), it does disrupt the ability to inhibit cellular iron release (PMID: 12429850), and causes partial loss of HFE function and increased hepatic iron loading in mice (PMID: 14673107). For these reasons, this variant has been classified as Pathogenic (low penetrance).
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000000026 SCV000223933 pathogenic Hemochromatosis type 1 2016-01-27 criteria provided, single submitter clinical testing The c.187C>G (p.His63Asp) missense variant is widely recognized as one of the two most common disease-causing variants in the HFE gene. Compound heterozygotes for p.Cys282Tyr and p.His63Asp are common in the Caucasian population, and together with homozygotes for the p.Cys282Tyr, account for 87% of individuals of European origin with HFE-HH. However, it is important to note that only ~ 0.5%-2.0% of compound heterozygous individuals develop clinical evidence of the disease due to incomplete penetrance (GeneReviews: Seckington et al., 2015; Ramrakhiani and Bacon, 1998; Morrison et al., 2003). In summary, this variant c.187C>G, (p.His63Asp) meets our criteria for Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000175607 SCV000227124 other not provided 2018-06-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000394716 SCV000461883 pathogenic Hereditary hemochromatosis 2016-06-14 criteria provided, single submitter clinical testing The c.187C>G (p.His63Asp) variant is well described in the literature as a pathogenic variant with significantly reduced penetrance (Seckington et al. 2015). Only two percent or fewer of individuals who are homozygous or compound heterozygous for the p.His63Asp variant are expected to develop clinical symptoms of hereditary hemochromatosis (HH) (Gochee et al. 2002; Gurrin et al. 2009; Gallego et al. 2015). The p.His63Asp variant was first reported by Feder et al. (1996) in a cohort of 178 HH patients in one homozygote, eight compound heterozygotes, and nine heterozygotes where a second variant was not observed. This variant was also found in 51 of 308 control chromosomes in this study. The p.His63Asp variant is reported at a frequency of 0.25234 in the Iberian Population in Spain in the 1000 Genomes Project. This allele frequency is high but is consistent with disease prevalence, reduced penetrance, and a mild phenotype. Based on the evidence, the p.His63Asp variant is classified as a pathogenic variant with significantly reduced penetrance for hereditary hemochromatosis.
GeneDx RCV000175607 SCV000577565 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing The H63D variant in the HFE gene is a common variant associated with hereditary hemochromatosis. When present in the homozygous state, H63D is associated with elevated serum transferrin and transferrin saturation, but the presence of clinical symptoms and iron overload was not increased compared to individuals without an HFE variant (Gochee et al., 2002; Feder et al., 1996). The H63D variant may be more clinically relevant when present in the compound heterozygous state with the C282Y variant, although most individuals do not develop clinical hemochromatosis symptoms, even if they have biochemical parameters consistent with hemochromatosis (Gurrin et al., 2009; Seckington and Powell, 2015). The H63D variant is observed in 18,253/126,698 alleles (14.4%) from individuals of European background, and 30,021/277,190 global alleles (10.8%) including 1992 homozygous control individuals, in large population cohorts (Lek et al., 2016). The H63D 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 H63D disrupts normal protein function (Nandar et al., 2013; Mitchell et al., 2011). We interpret H63D as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000000026 SCV000693430 pathogenic Hemochromatosis type 1 2015-09-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763144 SCV000893709 pathogenic Alzheimer disease; Variegate porphyria; Microvascular complications of diabetes 7; Hemochromatosis type 1; Transferrin serum level quantitative trait locus 2; Familial porphyria cutanea tarda 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000000026 SCV001137061 pathogenic Hemochromatosis type 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000175607 SCV001154674 likely benign not provided 2020-01-01 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000000026 SCV001194094 pathogenic Hemochromatosis type 1 2019-12-26 criteria provided, single submitter clinical testing NM_000410.3(HFE):c.187C>G(H63D) is classified as pathogenic in the context of HFE-associated hereditary hemochromatosis. H63D is only associated with clinical hemochromatosis in the presence of some other genetic variant or condition that affects iron metabolism such as the C282Y variant or liver disease. Sources cited for classification include the following: PMID 9462220, 11904676, 11358905, 19159930, 19554541 and 14673107. Classification of NM_000410.3(HFE):c.187C>G(H63D) 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.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000000026 SCV001251532 pathogenic Hemochromatosis type 1 criteria provided, single submitter research The HFE c.187C>G (p.H63D) variant is a pathogenic variant seen in 10.8% of the human population in gnomAD. Indviduals with the p.H63D variant are considered carriers of hemochromatosis, although this variant is associated with less severe iron overload and reduced penetrance compared to another pathogenic HFE variant, c.845G>A, p.C282Y (PMID: 19159930; 20301613).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197569 SCV001368348 pathogenic Diabetes mellitus type 2; Restrictive cardiomyopathy; Increased serum ferritin; Elevated transferrin saturation; Elevated hepatic iron concentration 2018-09-25 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,PP2,PP3. This variant was detected in hemizygous state.
OMIM RCV000000026 SCV000020169 pathogenic Hemochromatosis type 1 2018-05-02 no assertion criteria provided literature only
OMIM RCV000000027 SCV000020170 risk factor Microvascular complications of diabetes 7 2008-09-01 no assertion criteria provided literature only
GeneReviews RCV000000026 SCV000245789 pathogenic Hemochromatosis type 1 2015-09-17 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV001248831 SCV000607203 not provided Bronze diabetes no assertion provided phenotyping only Variant interpretted as Pathogenic and , most recently, reported on 4-24-2019 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.
Center for Computational Genomics and Data Science,University of Alabama RCV000991133 SCV001142520 risk factor Cystic fibrosis 2019-04-01 no assertion criteria provided research

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