Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001009653 | SCV001169746 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-03-25 | criteria provided, single submitter | clinical testing | The p.S334G variant (also known as c.1000A>G), located in coding exon 7 of the FH gene, results from an A to G substitution at nucleotide position 1000. The serine at codon 334 is replaced by glycine, an amino acid with similar properties. A similar alteration affecting this same amino acid, p.S334R has been reported in an individual with histologically confirmed cutaneous leiomyomata (Badeloe S et al. J. Dermatol. Sci. 2008; 51:139-43), and p.S334R was shown to segregate with disease within this family as it was also detected in this individual's daughter with papillary renal cell carcinoma at age 18 (van Spaendonck-Zwarts K et al. Fam Cancer. 2012 Mar;11(1):123-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV002549302 | SCV003243856 | uncertain significance | not provided | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 334 of the FH protein (p.Ser334Gly). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 818243). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |