ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2287G>A (p.Ala763Thr) (rs777004957)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414262 SCV000491854 uncertain significance not specified 2016-11-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSC2 gene. The A763T variant has been previously reported in at least one individual in association with HCM (Lopes et al., 2013; Lopes et al., 2015); however, Lopes et al. (2013) reported this individual harbored two additional cardiogenetic variants, including a nonsense variant in the MYBPC3 gene, and no segregation studies were reported. The A763T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the A763T 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. Nevertheless, this substitution occurs at a position that is not conserved across species and Threonine is tolerated at this position in multiple species. Furthemore, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000695038 SCV000823513 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 763 of the DSC2 protein (p.Ala763Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs777004957, ExAC 0.02%). This variant has been reported in the literature in an individual affected with hypertrophic cardiomyopathy who also had a pathogenic variant in a different gene, which suggests that this variant was not the primary cause of disease in this individual (PMID: 23396983). ClinVar contains an entry for this variant (Variation ID: 373271). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.