Submissions for variant NM_001943.5(DSG2):c.1439C>T (p.Thr480Ile)

gnomAD frequency: 0.00001  dbSNP: rs1598819592

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820110	SCV000960804	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 480 of the DSG2 protein (p.Thr480Ile). This variant is not present in population databases (gnomAD no frequency). 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: 662464). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 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.
Color Diagnostics, LLC DBA Color Health	RCV001188393	SCV001355450	uncertain significance	Cardiomyopathy	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 480 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223953	SCV002503189	uncertain significance	not provided	2021-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390687	SCV002699328	uncertain significance	Cardiovascular phenotype	2021-11-24	criteria provided, single submitter	clinical testing	The p.T480I variant (also known as c.1439C>T), located in coding exon 11 of the DSG2 gene, results from a C to T substitution at nucleotide position 1439. The threonine at codon 480 is replaced by isoleucine, an amino acid with similar properties. This variant was initially reported in an asymptomatic individual from an arrhythmogenic right ventricular cardiomyopathy (ARVC) variant study, who had normal transthoracic echocardiography results and also had a PKP2 variant detected (Perrin MJ et al. J Am Coll Cardiol, 2013 Nov;62:1772-9). This variant has also been reported in arrhythmia cohorts; however, clinical details were limited (Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440; VanDyke RE et al. J Genet Couns, 2021 04;30:503-512). 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 alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002487829	SCV002776940	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-07-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002820	SCV004819536	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 480 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.