Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Broad Center for Mendelian Genomics, |
RCV001004960 | SCV001164497 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2B | 2018-12-03 | criteria provided, single submitter | research | The heterozygous p.Pro1974Leu variant in DYSF was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a likely pathogenic variant and in an individual with LGMD increases the likelihood that the p.Pro1974Leu variant is pathogenic. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of p.Pro1974Leu is uncertain. ACMG/AMP Criteria applied: PM2, PM3_Supporting (Richards 2015). |
Invitae | RCV003574818 | SCV004292582 | likely pathogenic | Qualitative or quantitative defects of dysferlin | 2022-12-14 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 813969). This missense change has been observed in individuals with clinical features of limb-girdle muscular dystrophy (PMID: 26060040; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1935 of the DYSF protein (p.Pro1935Leu). |