ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.734A>C (p.Glu245Ala) (rs373201722)

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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 RCV000171895 SCV000050900 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171895 SCV000517880 uncertain significance not provided 2018-04-30 criteria provided, single submitter clinical testing The E245A variant in the DSC2 gene has been published in one presumably healthy control individual (Kapplinger et al., 2011). This variant is also observed in 8/24,008 alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The E245A variant has been identified in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, at least two of whom also harbor a pathogenic variant in another gene. So far, segregation data is limited or absent for these individuals due to insufficient participation by informative family members. Nevertheless, the E245A 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. 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 benign.
Invitae RCV000644635 SCV000766338 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2017-08-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 245 of the DSC2 protein (p.Glu245Ala). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs373201722, ExAC 0.04%). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 191624). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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