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

gnomAD frequency: 0.00001  dbSNP: rs141388237

Total submissions: 5

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.
Labcorp Genetics (formerly Invitae), Labcorp	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.
All of Us Research Program, National Institutes of Health	RCV003997673	SCV004821756	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-03-28	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.