ClinVar Miner

Submissions for variant NM_000410.4(HFE):c.502G>C (p.Glu168Gln)

gnomAD frequency: 0.00102  dbSNP: rs146519482
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208047 SCV000263951 uncertain significance Hemochromatosis type 1 2015-11-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000557367 SCV000633733 uncertain significance Hereditary hemochromatosis 2025-01-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 168 of the HFE protein (p.Glu168Gln). This variant is present in population databases (rs146519482, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hemochromatosis (PMID: 10953950, 12681966, 15025725, 15477198, 19214108, 19787796). ClinVar contains an entry for this variant (Variation ID: 222651). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HFE protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Precision Medicine, Vanderbilt University Medical Center RCV000208047 SCV000889988 uncertain significance Hemochromatosis type 1 2018-03-16 criteria provided, single submitter research
CeGaT Center for Human Genetics Tuebingen RCV000998548 SCV001154677 uncertain significance not provided 2023-03-01 criteria provided, single submitter clinical testing HFE: PM2, BP4
Illumina Laboratory Services, Illumina RCV000208047 SCV001319374 uncertain significance Hemochromatosis type 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx RCV000998548 SCV001804916 uncertain significance not provided 2024-07-18 criteria provided, single submitter clinical testing Identified in individuals with hereditary hemochromatosis; however, all reported individuals also harbored other variants in the HFE gene and it remains unclear whether this variant is sufficient to cause disease (PMID: 10953950, 12537660, 12681966, 15477198, 19214108, 19787796); Identified in a patient with hyperferritinemia and analyses suggested this variant was in cis with the p.(His63Asp) variant (PMID: 29084376); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12870733, 12681966, 15477198, 12537660, 12952143, 15025725, 19214108, 19787796, 29590070, 34426522, 10953950, 19759876, 29084376)
Fulgent Genetics, Fulgent Genetics RCV002485360 SCV002776008 uncertain significance Variegate porphyria; Microvascular complications of diabetes, susceptibility to, 7; Alzheimer disease type 1; Hemochromatosis type 1; TRANSFERRIN SERUM LEVEL QUANTITATIVE TRAIT LOCUS 2; Familial porphyria cutanea tarda 2021-11-22 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000208047 SCV003801493 uncertain significance Hemochromatosis type 1 2023-02-08 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000998548 SCV004227200 uncertain significance not provided 2022-11-29 criteria provided, single submitter clinical testing BP4

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