ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2110A>G (p.Ile704Val)

gnomAD frequency: 0.00001  dbSNP: rs141388237
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208311 SCV000263855 uncertain significance Primary familial hypertrophic cardiomyopathy 2015-06-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001187851 SCV001354744 uncertain significance Cardiomyopathy 2019-11-27 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 704 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy, who also carried a pathogenic variant in the MYH7 gene (PMID: 23396983). This variant has been identified in 3/249432 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002415875 SCV002725967 uncertain significance Cardiovascular phenotype 2022-06-01 criteria provided, single submitter clinical testing The p.I704V variant (also known as c.2110A>G), located in coding exon 14 of the DSG2 gene, results from an A to G substitution at nucleotide position 2110. The isoleucine at codon 704 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited. (Lopes LR et al. J Med Genet, 2013 Apr;50:228-39). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV002517393 SCV003478973 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2022-07-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 704 of the DSG2 protein (p.Ile704Val). This variant is present in population databases (rs141388237, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 222563). 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 valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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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