ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.977A>T (p.Asp326Val) (rs769699241)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618341 SCV000736230 uncertain significance Cardiovascular phenotype 2016-03-30 criteria provided, single submitter clinical testing The p.D326V variant (also known as c.977A>T), located in coding exon 8 of the DSG2 gene, results from an A to T substitution at nucleotide position 977. The aspartic acid at codon 326 is replaced by valine, an amino acid with highly dissimilar properties. This variant was detected in a patient reported to havearrhythmogenicright ventricular dysplasia/cardiomyopathy, who also had a nonsense alteration in thePKP2 gene (FressartV et al.Europace.2010;12(6):861-8).Based on data fromExAC, the T allele was reported in 2 of120684 (0.001%) total alleles(ExomeAggregation Consortium (ExAC), Cambridge, MA (URL: [Accessed March 21, 2016]).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5971 samples (11942 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV001067163 SCV001232206 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 326 of the DSG2 protein (p.Asp326Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs769699241, ExAC 0.02%). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443). ClinVar contains an entry for this variant (Variation ID: 518781). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). 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. 5

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