Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002563924 | SCV001411624 | pathogenic | not provided | 2023-07-06 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 964551). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function. This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer (PMID: 14632190; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 158 of the FH protein (p.Ser158Ile). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004699225 | SCV005203774 | uncertain significance | not specified | 2024-07-30 | criteria provided, single submitter | clinical testing | Variant summary: FH c.473G>T (p.Ser158Ile), also reported as S115I, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251276 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.473G>T has been reported in the literature in at least 1 individual affected with clinical features of Hereditary Leiomyomatosis And Renal Cell Cancer (example, Martinez-Mir_2003). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 14632190). ClinVar contains an entry for this variant (Variation ID: 964551). Based on the evidence outlined above, the variant was classified as uncertain significance. |