Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Molecular Genetics, |
RCV002225155 | SCV002503641 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2B | 2024-02-05 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace arginine with glutamine at codon 236 of the DYSF protein, p.(Arg236Gln). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is located in the C2 domain 2. There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (3/30,616 alleles) in the South Asian population, which is consistent with recessive disease. To our knowledge, this variant has not been previously reported in the relevant scientific literature. Computational evidence is uninformative for the missense substitution (REVEL=0.334). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting. |
Invitae | RCV003093885 | SCV003255492 | uncertain significance | Qualitative or quantitative defects of dysferlin | 2022-06-17 | 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 204 of the DYSF protein (p.Arg204Gln). This variant is present in population databases (rs528386282, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. 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 not expected to disrupt DYSF 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. |