Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002562557 | SCV001394724 | uncertain significance | not provided | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 421 of the FH protein (p.Arg421Met). This variant is not present in population databases (gnomAD no frequency). 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: 950816). 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%. 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. |
Ambry Genetics | RCV002447119 | SCV002676680 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-11-09 | criteria provided, single submitter | clinical testing | The p.R421M variant (also known as c.1262G>T), located in coding exon 9 of the FH gene, results from a G to T substitution at nucleotide position 1262. The arginine at codon 421 is replaced by methionine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Natera, |
RCV001222615 | SCV002085298 | uncertain significance | Fumarase deficiency | 2020-03-20 | no assertion criteria provided | clinical testing |