ClinVar Miner

Submissions for variant NM_001927.4(DES):c.376G>T (p.Val126Leu)

dbSNP: rs876657770
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000214253 SCV000271621 uncertain significance not specified 2015-10-22 criteria provided, single submitter clinical testing The p.Val126Leu variant in DES has not been previously reported in individuals w ith cardiomyopathy. Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation analysis suggest that the p.Val126Leu variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, t he clinical significance of the p.Val126Leu variant is uncertain.
Invitae RCV000820863 SCV000961596 uncertain significance Desmin-related myofibrillar myopathy 2023-07-07 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 126 of the DES protein (p.Val126Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy or left ventricular noncompaction (PMID: 25163546, 32746448, 33500567). ClinVar contains an entry for this variant (Variation ID: 228549). 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 DES protein function.

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