Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002014091 | SCV002307344 | likely pathogenic | Qualitative or quantitative defects of dysferlin | 2024-04-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 959 of the DYSF protein (p.Arg959Gln). This variant is present in population databases (rs752689148, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 1510740). 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 DYSF protein function with a positive predictive value of 95%. This variant disrupts the p.Arg959 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14678801, 16934466, 17070050, 19528035, 21522182, 22194990). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| 3billion, |
RCV003314031 | SCV004013673 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2B | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.90). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with DYSF -related disorder (ClinVar ID: VCV001510740). A different missense change at the same codon (p.Arg977Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000284254 / PMID: 14678801). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |