Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001558848 | SCV001214331 | pathogenic | not provided | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 312 of the FH protein (p.Phe312Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hereditary leiomyomatosis and renal cell cancer (PMID: 21398687; Invitae). ClinVar contains an entry for this variant (Variation ID: 846829). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 21398687). This variant disrupts the p.Phe312 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9635293; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001558848 | SCV001780877 | likely pathogenic | not provided | 2020-01-22 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Also known as c.806T>C, p.Phe269Ser; This variant is associated with the following publications: (PMID: 27240081, 21398687) |
| Ambry Genetics | RCV002445265 | SCV002682338 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-07-08 | criteria provided, single submitter | clinical testing | The p.F312S pathogenic mutation (also known as c.935T>C), located in coding exon 7 of the FH gene, results from a T to C substitution at nucleotide position 935. The phenylalanine at codon 312 is replaced by serine, an amino acid with highly dissimilar properties. Another alteration at the same codon, p.F312L (c.934T>C), co-segregated with disease in 4/4 individuals from one family tested in our laboratory (Ambry internal data). The p.F312S alteration has been observed in at least one individual with a personal and/or family history that is consistent with HLRCC-related disease (Ambry internal data). This variant (previously designated as p.Phe269Ser) has also been identified in the literature in an individual with suspected HLRCC; FH activity from lymphoblastoid cell lines from this individual was 36% compared to wildtype (Gardie B et al. J Med Genet, 2011 Apr;48:226-34). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |