Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002545560 | SCV002300524 | uncertain significance | not provided | 2023-12-04 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 266 of the FH protein (p.Met266Thr). This variant is present in population databases (rs764648497, gnomAD 0.02%). 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: 1510249). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. |
| Ambry Genetics | RCV002423251 | SCV002677209 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-10-24 | criteria provided, single submitter | clinical testing | The p.M266T variant (also known as c.797T>C), located in coding exon 6 of the FH gene, results from a T to C substitution at nucleotide position 797. The methionine at codon 266 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 4500 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is not well 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 p.M266T remains unclear. |
| Laboratory of Molecular Epidemiology of Birth Defects, |
RCV003154232 | SCV003843778 | likely pathogenic | Ovarian cancer | 2022-01-01 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003471264 | SCV004197339 | uncertain significance | Fumarase deficiency | 2023-07-28 | criteria provided, single submitter | clinical testing |