ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1003A>G (p.Thr335Ala) (rs191564916)

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Total submissions: 17
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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, Partners HealthCare 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.
Blueprint Genetics RCV000157183 SCV000206907 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-12-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000656843 SCV000232621 uncertain significance not provided 2014-11-12 criteria provided, single submitter clinical testing
GeneDx RCV000656843 SCV000233491 uncertain significance not provided 2018-04-16 criteria provided, single submitter clinical testing The T335A variant of uncertain significance in the DSG2 gene has been reported in multiple heterozygous individuals in association with ARVD/C (den Haan et al., 2009; Christensen et al., 2010; Campian et al., 2011; Kapplinger et al., 2011; Quarta et al., 2011; Rasmussen et al., 2013; Green et al., 2015; Medeiros- Domingos et al., 2016). In several cases, the individuals harbored additional cardiogenetic variants (den Haan et al., 2009; Kapplinger et al, 2011; Medeiros-Domingos et al., 2016), although segregation data were not available. Rasmussen et al. (2013) reported two siblings with severe ARVD/C and normal hair/skin findings who were both homozygous for the T335A variant; however, their heterozygous relatives were reportedly unaffected. The T335A variant has also been reported in association with dilated cardiomyopathy (DCM) in two families (Garcia-Pavia et al., 2011; Pugh et al., 2014), and was reported to segregate with DCM in one relative (Garcia-Pavia et al., 2011). In addition, this variant was found in one male individual with Brugada syndrome, although his two relatives with positive flecainide tests did not harbor this variant (Allegue et al., 2015). Furthermore, T335A has been reported in two unrelated individuals with sudden unexplained death; however, they were also found to harbor additional variants in genes associated with sudden cardiac arrest (Sanchez et al., 2016). The T335A variant has also been identified both independently and in conjunction with additional cardiogenetic variants in multiple unrelated individuals referred for cardiomyopathy and/or arrhythmia genetic testing at GeneDx. In one individual with ARVD/C, T335A segregated with ARVD/C in two relatives; however, no informative segregation data is available for the remaining individuals referred for genetic testing at GeneDx. This variant has been observed at a frequency of approximately 0.05% (141/277086) of alleles from individuals in large population cohorts (Lek et al., 2016). Furthermore, T335A was found in 0.17% (3/1738) of alleles from a cohort of individuals not selected for arrhythmia, cardiomyopathy, or sudden death who underwent exome testing (Ng et al., 2013); however, follow-up cardiac exams were not reported. The T335A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV001034652 SCV000287229 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 335 of the DSG2 protein (p.Thr335Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs191564916, ExAC 0.09%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in the homozygous state in several individuals with arrhythmogenic right ventricular cardiomyopathy, whose heterozygous relatives were unaffected (PMID: 23381804, 23871674, 24704780, 25445213, 28818065). This variant has also been observed in the heterozygous state in several individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20031617, 23381804, 20864495, 21606390, 21636032, 20152563, 21636032, 30790397) and in 2 individuals with dilated cardiomyopathy (PMID: 21859740, 24503780). However, in several heterozygous individuals pathogenic alleles were also identified in a different gene, which suggests that this c.1003A>G variant may not be the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 44278). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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 uncertain significance Cardiovascular phenotype 2020-03-18 criteria provided, single submitter clinical testing The p.T335A variant (also known as c.1003A>G), located in coding exon 8 of the DSG2 gene, results from an A to G substitution at nucleotide position 1003. The threonine at codon 335 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (den Haan AD et al, Circ Cardiovasc Genet 2009 Oct; 2(5):428-35; Christensen AH et al, J. Med. Genet. 2010 Nov; 47(11):736-44; Cox MG et al, Circulation 2011 Jun; 123(23):2690-700; Quarta G et al, Circulation 2011 Jun; 123(23):2701-9; Te Riele AS et al, J. Cardiovasc. Electrophysiol. 2013 Dec; 24(12):1311-20; Ng D et al, Circ Cardiovasc Genet 2013 Aug; 6(4):337-46), and also in patients with dilated cardiomyopathy (Garcia-Pavia P et al, Heart 2011 Nov; 97(21):1744-52; Pugh TJ et al, Genet. Med. 2014 Aug; 16(8):601-8). These reported patients generally had additional alterations in other cardiac-related genes. This variant has also been detected in the homozygous state in several ARVC patients and as heterozygous in their unaffected relatives, suggesting autosomal recessive inheritance of the alteration (internal Ambry data; Groeneweg JA et al. Am. J. Cardiol. 2013;112(8):1197-206; Rasmussen TB et al. Hum. Mutat. 2013 May; 34(5):697-705; Qadri S et al. BMC Med. Genet., 2017 08;18:86). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Internal structural analysis indicates that this variant, located in the third cadherin repeat domain, is surface exposed, not on a dimerization interface, and appears to have a neutral impact. Based on population frequency, clinical presentation, and structural analysis, the clinical significance of this alteration remains unclear.
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 Health, Inc 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 Praxis fuer Humangenetik Tuebingen RCV000656843 SCV001151513 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001034652 SCV001283481 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 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 cardiomyopathy, type 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 likely benign not specified 2020-12-29 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. The observed variant frequency is approximately 2.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00025), strongly suggesting that the variant is benign. c.1003A>G has been reported in the literature in studies reporting individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (example, denHaan_2009, Xu_2010, Christensen_2010, Tan_2010, Cox_2011, Garcia-Pavia_2011, Quarta_2011, Groeneweg_2013, Rasmussen_2013, teRiele_2013, Hermida_2019). Some of the probands reported no family history of ARVD despite a homozygous affected genotype and cite an ACMG classification reporting questionable classification criteria (example, Hermida_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Several co-occurrences with other pathogenic variant(s) have been reported in the literature as well as in our own testing experience (ARVD, PKP2 c.145_148delCAGA, p.Thr50fs; PKP2 c.235C>T, p.Arg79* in the literature; LQT1, KCNQ1 c.1075C>T, p.Q359* at our laboratory), 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 (Rasmussen_2013). Thirteen 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 while some cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
Genomics England Pilot Project,Genomics England RCV001034652 SCV001760428 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 no assertion criteria provided clinical testing

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