Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000166376 | SCV000217167 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-05-10 | criteria provided, single submitter | clinical testing | The p.I262R variant (also known as c.785T>G), located in coding exon 6 of the FH gene, results from a T to G substitution at nucleotide position 785. This variant was reported in multiple individuals with features consistent with Hereditary leiomyomatosis and renal cell cancer (external communication; Ambry internal data). The isoleucine at codon 262 is replaced by arginine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is also predicted to be destabilizing to the protein structure (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Gene |
RCV001577505 | SCV001804894 | uncertain significance | not provided | 2019-07-31 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
| Labcorp Genetics |
RCV001577505 | SCV002205678 | uncertain significance | not provided | 2024-04-02 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 262 of the FH protein (p.Ile262Arg). 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: 186733). 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. |