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

gnomAD frequency: 0.00004  dbSNP: rs769713919

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000241707	SCV000318242	uncertain significance	Cardiovascular phenotype	2022-12-21	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 and in an individual with hearing loss; however, clinical details were limited and additional variants were detected (Bottillo I et al. Gene, 2016 Feb;577:227-35; Zhou Y et al. BMC Med Genet. 2020 Jul;21(1):151). 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 amino acid position is highly 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.
Laboratory for Molecular Medicine, Mass General Brigham 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 dysplasia 10	2024-01-18	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 70 of the DSG2 protein (p.Ile70Val). This variant is present in population databases (rs769713919, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 22458570, 26656175). ClinVar contains an entry for this variant (Variation ID: 263501). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001191582	SCV001359452	uncertain significance	Cardiomyopathy	2023-12-12	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.
Fulgent Genetics, Fulgent Genetics	RCV002494783	SCV002797618	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2022-02-08	criteria provided, single submitter	clinical testing