ClinVar Miner

Submissions for variant NM_000410.3(HFE):c.193A>T (p.Ser65Cys) (rs1800730)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000000028 SCV000206974 pathogenic Hemochromatosis type 1 2014-11-11 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764641 SCV000895749 uncertain significance Alzheimer's 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
GeneReviews RCV000000028 SCV000245790 pathogenic Hemochromatosis type 1 2015-09-17 no assertion criteria provided literature only
Illumina Clinical Services Laboratory,Illumina RCV000000028 SCV000461884 uncertain significance Hemochromatosis type 1 2017-07-27 criteria provided, single submitter clinical testing The HFE c.193A>T (p.Ser65Cys) variant is a missense variant that has been reported to be enriched in individuals affected with hereditary hemochromatosis as compared to unaffected individuals in two studies (Mura et al. 1999; Holmstrom et al. 2002). The authors suggested that the p.Ser65Cys variant is associated with a mild phenotype, resulting in a lower degree of iron overload as compared to common pathogenic variants in the HFE gene. Two functional studies have reported that the p.Ser65Cys variant alone has no significant influence on iron status markers (Pedersen et al. 2009; Aranda et al. 2010), and Bacon et al. (2011) and Alves et al. (2016) discuss that the p.Ser65Cys variant is generally not associated with iron loading unless seen in a compound heterozygous state with either the p.Cys282Tyr or p.His63Asp variant. The p.Ser65Cys variant is reported at a frequency of 0.03846 in the British of England and Scotland population of the 1000 Genomes Project, which is consistent with estimates of disease prevalence and penetrance. Although p.Ser65Cys variant is widely reported in the literature as the third most common variant associated with HFE-related hereditary hemochromatosis (Seckington et al. 2015), the functional evidence suggests that this variant may not contribute to the mechanism of disease. Based on this conflicting evidence, the p.Ser65Cys is classified as a variant of unknown significance but suspicious for pathogenicity for hereditary hemochromatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000290779 SCV000254532 uncertain significance Hereditary hemochromatosis 2018-12-15 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 65 of the HFE protein (p.Ser65Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This is a common variant that has been suggested to contribute to hemochromatosis when present with a second pathogenic allele in HFE (PMID: 10194428), but other studies have not found this association (PMID: 10660483, 19159930). For more information about the molecular genetics associated with hemochromatosis, see PMID: 16132052. Because the clinical significance of this variant is unclear at this time, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000000028 SCV000020171 pathogenic Hemochromatosis type 1 1999-04-15 no assertion criteria provided literature only

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