Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001018919 | SCV001180215 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-06-15 | criteria provided, single submitter | clinical testing | The p.F305S pathogenic mutation (also known as c.914T>C), located in coding exon 7 of the FH gene, results from a T to C substitution at nucleotide position 914. The phenylalanine at codon 305 is replaced by serine, an amino acid with highly dissimilar properties. This alteration has been observed in at least one individual who has a personal or family history that is consistent with FH-associated disease (Ambry internal data; Breen KE et al. Mol Genet Genomic Med, 2020 08;8:e1293; Truong H et al. Eur Urol Oncol, 2021 Dec;4:993-1000). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Pereira de Pádua RA et al. Acta Crystallogr F Struct Biol Commun, 2014 Jan;70:120-2). 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 variant is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV002549490 | SCV001378110 | pathogenic | not provided | 2023-08-01 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 305 of the FH protein (p.Phe305Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with uterine fibroids and renal cancer (PMID: 32463173; Invitae). ClinVar contains an entry for this variant (Variation ID: 823050). 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. |
| Gene |
RCV002549490 | SCV004167685 | likely pathogenic | not provided | 2023-10-12 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28873162, 29905933, 24419633, 34654685, 32463173) |