ClinVar Miner

Submissions for variant NM_001927.4(DES):c.679C>T (p.Arg227Cys)

gnomAD frequency: 0.00001  dbSNP: rs767743962
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000468464 SCV000552167 likely pathogenic Desmin-related myofibrillar myopathy 2025-01-26 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 227 of the DES protein (p.Arg227Cys). This variant is present in population databases (rs767743962, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant dilated cardiomyopathy (PMID: 28171858). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411141). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DES protein function with a positive predictive value of 95%. 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, Medical Genetics RCV001809412 SCV002058134 uncertain significance Neurogenic scapuloperoneal syndrome, Kaeser type 2022-01-03 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: 0.000008, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.734, PP3_P). A missense variant is a common mechanism associated with Scapuloperoneal syndrome (PP2_P). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
GeneDx RCV004719831 SCV005325916 uncertain significance not provided 2024-02-05 criteria provided, single submitter clinical testing Identified in a family with dilated cardiomyopathy in the literature, although additional variants in other cardiomyopathy genes were found in this family and detailed familial segregation data was not provided (PMID: 28171858); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33823640, 26807690, 28171858)

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