Submissions for variant NM_001943.5(DSG2):c.1003A>G (p.Thr335Ala)

gnomAD frequency: 0.00060  dbSNP: rs191564916

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000157183	SCV000051374	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037261	SCV000060918	uncertain significance	not specified	2019-01-29	criteria provided, single submitter	clinical testing	The p.Thr335Ala variant in DSG2 has been reported in 2 individuals with DCM, 3 individuals with sudden death, >15 individuals with ARVC (4 of these individuals also carried an additional disease-causing variant), and 3 families with an apparently recessive form of ARVC (affected homozygous siblings and unaffected heterozygous parents/siblings; den Haan 2009, Xu 2010, Christensen 2010, Quarta 2011, Cox 2011, Garcia-Pavia 2011, Rasmussen 2013, Duong 2017, Groneweg 2013, Green 2015, Calore 2012 (Master's thesis), Mederios-Domingo 2017, Qadri 2017, Schymanski 2017 (Master's thesis), Sanchez 2016, LMM data). This variant has been identified in 0.1% (29/25792) of Finnish and 0.06% (84/126612) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs191564916). This variant has also been reported in ClinVar (Variation ID 44278). Computational prediction tools and conservation analysis suggest that the p.Thr335Ala variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr335Ala variant is uncertain due to conflicting data. The ACMG/AMP Criteria applied: PS4, PP1_M, BP4, BP5.
Eurofins Ntd Llc (ga)	RCV000656843	SCV000232621	uncertain significance	not provided	2014-11-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000656843	SCV000233491	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Reported in multiple heterozygous individuals in association with ARVD/C, dilated cardiomyopathy (DCM), Brugada syndrome and sudden unexplained death (den Haan et al., 2009; Christensen et al., 2010; Campian et al., 2011; Kapplinger et al., 2011; Quarta et al., 2011; Garcia-Pavia et al., 2011; Rasmussen et al., 2013; Pugh et al., 2014; Green et al., 2015; Allegue et al., 2015; Medeiros- Domingos et al., 2016; Sanchez et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26230511, 23871885, 33968641, 33232181, 33673806, 33652588, 32917565, 33919104, 23861362, 23299917, 24585727, 20864495, 20857253, 20152563, 21859740, 21553091, 21606396, 21636032, 23810894, 24503780, 24704780, 21606390, 27194543, 25445213, 27930701, 28341588, 28818065, 30790397, 29802319, 29606362, 31712859, 31737537, 31402444, Bueno-Beti2022, 35061126, 28255936, 23871674, 32746448, 20031617, 23381804, 34758253, 35653365, 35712781, 36139162)
Invitae	RCV001034652	SCV000287229	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 335 of the DSG2 protein (p.Thr335Ala). This variant is present in population databases (rs191564916, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (PMID: 20031617, 20152563, 20864495, 21606390, 21636032, 23381804, 23871674, 24704780, 25445213, 28818065, 30790397). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44278). 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.
Ambry Genetics	RCV000252861	SCV000318785	likely benign	Cardiovascular phenotype	2022-05-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000037261	SCV000747936	uncertain significance	not specified	2017-07-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656843	SCV000885320	uncertain significance	not provided	2017-08-18	criteria provided, single submitter	clinical testing	One variant of uncertain clinical significance, c.1003A>G; p.Thr335Ala, was detected in the DSG2 gene by massively parallel sequencing and confirmed by Sanger sequencing. The c.1003A>G; p.Thr335Ala has been reported in patients with Arrhythmogenic right ventricular cardiomyopathy (ARVC) (Rasmussen et al. 2013, Christensen et al. 2010, den Haan et al. 2009, te Riele et al. 2013). Rasmussen (2013) observed homozygous brothers with ARVC who had unaffected heterozygote siblings and parents. Additionally, three heterozygote males with ARVC were reported in the same study with unaffected heterozygote parents. den Haan (2009) observed this variant in one heterozygote male with ARVC who also carried a loss of function variant in the PKP2 gene. This variant has also been reported in three patients with dilated cardiomyopathy (DCM) however with lack of segregation in the families (Garcia-Pavia et al. 2011, Pugh et al. 2014). Ng (2013) observed this variant with an allele frequency of 0.2 percent (on 3 out of 1,738 chromosomes) in individuals not selected for arrhythmia, cardiomyopathy, or a family history of sudden death and classified this variant likely benign. Rasmussen (2013) also demonstrated no significant changes in abundance or localization of the variant DSG2 protein by immuno-histochemical staining of myocardial or epidermal tissues. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.1 percent in the European Finnish population (identified on 29 out of 25,792 chromosomes), and is reported to the ClinVar database as a variant of uncertain significance (Variation ID: 44278). Given the overabundance of this variant in the control populations (from gnomAD) and, the reported cases of heterozygote patients and unaffected relatives with ARVC and DCM, it remains to be determined whether the p.Thr335Ala is a benign polymorphism or a pathogenic variant with low penetrance.
Color Diagnostics, LLC DBA Color Health	RCV000777939	SCV000914037	likely benign	Cardiomyopathy	2019-09-24	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000777939	SCV000995457	likely benign	Cardiomyopathy	2018-03-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656843	SCV001151513	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001034652	SCV001283481	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2018-08-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001034652	SCV001366836	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2019-09-07	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5,BP5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000656843	SCV001447080	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037261	SCV001467983	uncertain significance	not specified	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.1003A>G (p.Thr335Ala) results in a non-conservative amino acid change located in the Cadherin like domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 254132 control chromosomes (no homozygotes; gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00025), suggesting that the variant may be benign. c.1003A>G has been reported in the literature in multiple heterozygous individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g., denHaan_2009, Xu_2010, Christensen_2010, Tan_2010, Cox_2011, Garcia-Pavia_2011, Quarta_2011, Rasmussen_2013, teRiele_2013, Iglesias_2021, Hathaway_2021), however without strong evidence for causality (e.g., lack of co-segregation data, lack of segregation with disease in some families, or co-occurrence with pathogenic variants in other ARVC-associated genes). However, the variant has also been reported in the homozygous state in several ARVC patients (e.g., Groeneweg_2013, Rasmussen_2013, Hermida_2019, Qadri_2017), and the variant was shown to segregate with disease and displayed complete penetrance in an autosomal recessive inheritance pattern in five homozygotes from one family (Qadri_2017). These reports do not provide unequivocal conclusions about association of the variant with autosomal dominant Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, but suggest the variant may be associated with recessive disease. Several co-occurrences with other pathogenic variants have been reported in heterozygous individuals in the literature and observed in our own laboratory (ARVD, PKP2 c.145_148delCAGA, p.Thr50fs; PKP2 c.235C>T, p.Arg79* in the literature; LQT1, KCNQ1 c.1075C>T, p.Q359* via internal testing), providing supporting evidence for a benign role. At least one publication reporting experimental evidence evaluating an impact on protein function was ascertained, however, it does not allow convincing conclusions about the variant effect while reporting that the altered protein was expressed and incorporated into desmosomes (e.g., Rasmussen_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23299917, 20864495, 21606396, 21859740, 23871674, 33673806, 30790397, 33919104, 23861362, 28818065, 21606390, 23381804, 20857253, 20152563, 20031617, 23810894). Sixteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n = 11; likely benign, n = 2; likely pathogenic, n = 2), and some cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656843	SCV002541458	uncertain significance	not provided	2021-07-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777939	SCV003838126	uncertain significance	Cardiomyopathy	2023-03-15	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224120	SCV003919889	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-03-30	criteria provided, single submitter	clinical testing	DSG2 NM_001943.4 exon 8 p.Thr335Ala (c.1003A>G): This variant has been reported in the literature in multiple individuals with ARVC in the heterozygous state (den Haan 2009 PMID:20031617, Christensen 2010 PMID:20864495, Xu 2010 PMID:20152563, Kapplinger 2011 PMID:21636032, te Riele 2013 PMID:23810894, Green 2015 PMID:25445213, Medeiros-Domingo 2017 PMID:27194543) as well as at least 2 individuals with ARVC in the homozygous state, segregating with disease in 4 affected family members (Rasmussen 2013 PMID:23381804, Rasmussen 2014 PMID:24704780, Qadri 2017 PMID:28818065). Of note, the literature states that all heterozygous carrier relatives of these homozygous probands are unaffected. This variant has also been identified in 2 individuals with DCM, segregating with disease in 1 affected family member (Garcia-Pavia 2011 PMID:21859740, Pugh 2014 PMID:24503780). This variant is present in 0.1% (29/25792) Finnish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs191564916) and is present in ClinVar (Variation ID:44278). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies suggest that this variant may impact the protein (Rasmussen 2013 PMID:23381804). However, these studies may not accurately represent in vivo biological function. Due to contradictory evidence, the clinical significance of this variant is uncertain.
Blueprint Genetics	RCV000157183	SCV000206907	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2015-12-07	flagged submission	clinical testing
Genomics England Pilot Project, Genomics England	RCV001034652	SCV001760428	likely pathogenic	Arrhythmogenic right ventricular dysplasia 10		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001034652	SCV002075025	not provided	Arrhythmogenic right ventricular dysplasia 10		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-22-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.