Submissions for variant NM_001943.5(DSG2):c.880A>G (p.Lys294Glu)

gnomAD frequency: 0.00001  dbSNP: rs752432726

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455978	SCV000539031	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: 1 report, functional study does not predict impact; ExAC: 1/9800 African chromosomes
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642318	SCV000763987	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 294 of the DSG2 protein (p.Lys294Glu). This variant is present in population databases (rs752432726, gnomAD 0.005%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy and/or dilated cardiomyopathy (PMID: 16505173, 24070718, 34036930). ClinVar contains an entry for this variant (Variation ID: 199803). 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. Experimental studies have shown that this missense change does not substantially affect DSG2 function (PMID: 23071725, 30885746). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757178	SCV000885314	uncertain significance	not provided	2018-02-27	criteria provided, single submitter	clinical testing	The DSG2 c.880A>G; p.Lys294Glu variant (rs752432726; ClinVar ID 199803) has been reported in a single individual with arrhythmogenic right ventricular cardiomyopathy (Pilichou 2006); however, functional studies of this variant found no defects in prodomain cleavage, adhesion properties, or cellular localization compared to the wild-type protein (Gaertner 2012). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.002% (identified on 6 out of 277,042 chromosomes). The lysine at position 294 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Lys294Glu variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Lys294Glu variant cannot be determined with certainty.
Color Diagnostics, LLC DBA Color Health	RCV001177919	SCV001342231	uncertain significance	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 294 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). A functional study has shown that this variant does not impact prodomain cleavage, cellular localization, adhesion and protein binding properties of DSG2 protein (PMID: 23071725, 30885746). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718, 26138720), hypertrophic cardiomyopathy (PMID: 30847666), idiopathic dilated cardiomyopathy (PMID: 34036930), or sudden explained death (PMID: 26272908, 33762593). This variant has also been identified in 6/280794 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000757178	SCV001712936	uncertain significance	not provided	2020-01-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001177919	SCV003838786	uncertain significance	Cardiomyopathy	2021-11-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000845343	SCV004819489	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 294 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). A functional study has shown that this variant does not impact prodomain cleavage, cellular localization, adhesion and protein binding properties of DSG2 protein (PMID: 23071725, 30885746). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718, 26138720), hypertrophic cardiomyopathy (PMID: 30847666), idiopathic dilated cardiomyopathy (PMID: 34036930), or sudden explained death (PMID: 26272908, 33762593). This variant has also been identified in 6/280794 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	RCV004992055	SCV005575744	uncertain significance	Cardiovascular phenotype	2024-07-10	criteria provided, single submitter	clinical testing	The p.K294E variant (also known as c.880A>G), located in coding exon 8 of the DSG2 gene, results from an A to G substitution at nucleotide position 880. The lysine at codon 294 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM) and intrauterine fetal death (Pilichou K et al. Circulation, 2006 Mar;113:1171-9; Muin DA et al. Sci Rep, 2021 Mar;11:6737; Mehaney DA et al. Cardiol Young, 2022 Feb;32:295-300; Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799). The impact on protein function from functional studies is uncertain (Gaertner A et al. PLoS One, 2012 Oct;7:e47097; Debus JD et al. J Mol Cell Cardiol, 2019 Apr;129:303-313). This amino acid position is well 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845343	SCV000987390	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy		flagged submission	clinical testing
Clinical Genetics, Academic Medical Center	RCV000757178	SCV001921133	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000757178	SCV001973535	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000757178	SCV001979734	uncertain significance	not provided		no assertion criteria provided	clinical testing