ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000000026 SCV000206973 pathogenic Hemochromatosis type 1 2015-11-26 criteria provided, single submitter clinical testing
Counsyl RCV000000026 SCV000678027 pathogenic Hemochromatosis type 1 2015-12-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000175607 SCV000227124 other not provided 2018-06-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763144 SCV000893709 pathogenic 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
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.
GeneReviews RCV000000026 SCV000245789 pathogenic Hemochromatosis type 1 2015-09-17 no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000000026 SCV000693430 pathogenic Hemochromatosis type 1 2015-09-14 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000394716 SCV000607203 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.
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.
Invitae RCV000394716 SCV000219176 pathogenic Hereditary hemochromatosis 2019-01-09 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844708 SCV000198337 pathogenic Hemochromatosis type 2 2014-04-17 criteria provided, single submitter clinical testing The p.His63Asp variant in HFE is a well-established pathogenic variant for hered itary hemochromatosis (HH). Although it is considered pathogenic, the penetrance is significantly reduced. Biochemically, only 13% of p.His63Asp homozygotes and 17% of p.His63Asp/p.Cys282Tyr compound heterozygotes were shown to have elevate d transferrin saturation (Pederson 2009) and less than 5% of individuals with bi allelic pathogenic HFE variants exhibit clinical symptoms of HH (Beutler 2002, G urrin 2009). In summary, this variant meets criteria to be classified as pathoge nic for HH in an autosomal recessive pattern but with significantly reduced pene trance. ACMG/AMP Criteria applied: PS3; PS4; PM3.
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.