Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002563095 | SCV001398842 | pathogenic | not provided | 2023-02-04 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 954126). This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis (PMID: 31831373). 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 cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 434 of the FH protein (p.Cys434Arg). 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 variant disrupts the p.Cys434 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25004247; 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. |