ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1630A>C (p.Met544Leu) (rs201960323)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171909 SCV000050912 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000521366 SCV000620731 uncertain significance not specified 2017-09-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The M544L variant has been observed in at least one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013); however, a follow-up cardiac evaluation was not reported. The M544L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M544L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to methionine (M) are tolerated across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Color RCV000774660 SCV000908539 uncertain significance Cardiomyopathy 2018-04-16 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the plakin domain of the DSP protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/246138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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