ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.208A>G (p.Ile70Val) (rs769713919)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000241707 SCV000318242 uncertain significance Cardiovascular phenotype 2020-09-22 criteria provided, single submitter clinical testing The p.I70V variant (also known as c.208A>G), located in coding exon 3 of the DSG2 gene, results from an A to G substitution at nucleotide position 208. The isoleucine at codon 70 is replaced by valine, an amino acid with highly similar properties. This alteration was reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited and additional variants were detected (Bottillo I et al. Gene, 2016 Feb;577:227-35). Additionally, this variant was detected in a patient with arrhythmogenic right ventricular cardiomyopathy (ARVC) who also carried a pathogenic truncating mutation in PKP2. The patient's two clinically unaffected family members had either this alteration or the PKP2 truncating alteration. (Rajkumar et al. BMC Med Genet 2012;13:21). This variant was also observed in conjunction with a different PKP2 truncating alteration in a patient tested by our laboratory. This amino acid position is highly conserved in available vertebrate species; however, valine is the reference amino acid in other 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455401 SCV000539030 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only report in individual who also carried truncating PKP2 variant; ExAC: 3/16510 South Asian chromosomes
GeneDx RCV000766750 SCV000568227 uncertain significance not provided 2016-02-29 criteria provided, single submitter clinical testing The I70V variant of uncertain significance has been reported previously in one individual with ARVC who alsoharbored a nonsense variant in the PKP2 gene (Rajkumar et al., 2012). This variant has also been observed in oneother individual referred for arrhythmia testing at GeneDx, though segregation data is absent. The I70V variant wasnot observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. Although the I70V variantoccurs at a position that is conserved across species, it is a conservative amino acid substitution, which is not likelyto impact secondary protein structure as these residues share similar properties. Consequently, in silico analysis isinconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV001038406 SCV001201873 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-05-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 70 of the DSG2 protein (p.Ile70Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs769713919, ExAC 0.02%). This variant has been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy or hypertrophic cardiomyopathy; however, these individuals also carried variants in other disease-associated genes (PMID: 22458570, 26656175). ClinVar contains an entry for this variant (Variation ID: 263501). 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: Benign; Align-GVGD: Class C2). 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
Color Health, Inc RCV001191582 SCV001359452 uncertain significance Cardiomyopathy 2020-08-27 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 70 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic truncation variant in the PKP2 gene (PMID: 22458570). This variant has also been reported in an individual with hypertrophic cardiomyopathy (PMID: 26656175). This variant has been identified in 11/280880 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.

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