Description
Variant summary: HFE c.193A>T (p.Ser65Cys) results in a non-conservative amino acid change located in the MHC class I-like antigen recognition-like domain (IPR011161) 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 0.01 in 251490 control chromosomes in the gnomAD database, including 24 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in HFE causing Hemochromatosis Type 1 (0.01 vs 0.046), allowing no conclusion about variant significance. c.193A>T has been reported in association with Hemochromatosis Type 1 in at least one published study, in which the variant was enriched in individuals affected with Hemochromatosis who did not have two alleles with some combination of the more common disease mutations p.C282Y and p.H63D (e.g. Mura_1999). This data suggested a possibly pathogenic role for the p.S65C variant. However, the variant has also been found in compound heterozygosity with these other disease variants in controls, and additional studies did not find association of the variant with the Hemochromatosis phenotype (e.g. Arya_1999, Oliveira_2009, Pedersen_2009). At least one publication reported an association for the variant with mild to moderate changes in serum ferritin and/or transferrin levels in indivduals who were compound heterozygotes for this variant and one of the common disease variants, however these individuals did not have clinical symptoms of iron load typically found in patients diagnosed with Hemochromatosis Type 1 (e.g. Holmstrom_2002). These reports do not provide unequivocal conclusions about association of the variant with Hemochromatosis Type 1. To our knowledge, no conclusive experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) have cited the variant as uncertain significance (n=4) and likely pathogenic (n=1). Based on the majority concordance in its classification among peers in the field supported by the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
