ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.802A>G (p.Thr268Ala) (rs201015785)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154700 SCV000204379 uncertain significance not specified 2017-10-23 criteria provided, single submitter clinical testing The p.Thr268Ala variant in DSC2 has been identified by our laboratory in one ind ividual with infantile-onset DCM and has been identified in 0.01% (40/276986) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst; dbSNP rs201015785). Computational prediction tools and conservation a nalysis do not provide strong support for or against an impact to the protein. I n summary, the clinical significance of the p.Thr268Ala variant is uncertain. AC MG/AMP Criteria applied: None applied (Richards 2015).
GeneDx RCV000656842 SCV000233420 uncertain significance not provided 2018-04-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSC2 gene. The T268A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 22/126566 (0.02%) alleles from individuals of European (non-Finnish) ancestry and in 7/34376 (0.02%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016). Nevertheless, the T268A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000252152 SCV000318264 uncertain significance Cardiovascular phenotype 2013-02-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000466138 SCV000551495 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 268 of the DSC2 protein (p.Thr268Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs201015785, ExAC 0.03%) but has not been reported in the literature in individuals with a DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 178019). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000466138 SCV000744769 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2015-09-21 criteria provided, single submitter clinical testing
Color RCV000777997 SCV000914104 uncertain significance Cardiomyopathy 2018-10-29 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the extracellular cadherin domain 2 of the DSC2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 40/276986 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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