Submissions for variant NM_024422.6(DSC2):c.631-2A>G

gnomAD frequency: 0.00001  dbSNP: rs397514042

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211713	SCV000063121	uncertain significance	not specified	2018-08-28	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The c.631-2A>G variant in DSC2 has been reported in 2 individuals with ARVC and 1 individual wi th LVNC (Heuser 2006, LMM data). It was also reported in a 110-year-old individu al (Gierman 2014) and in ClinVar (Variation ID: 16850). This variant has been id entified in 4/111556 European chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org). This variant occurs in the invariant re gion (+/- 1,2) of the splice consensus sequence, and in vitro studies confirmed that it leads to aberrant splicing and reduced DSC2 protein levels (Heuser 2006) . Splice and other loss-of-function variants in DSC2 have been reported in indiv iduals with ARVC; however, the clinical significance of these variants is not ye t fully understood. Although ARVC has primarily been described as a dominant dis order, in several reports of loss-of function variants, only those individuals w ith a variant on the second allele were affected, suggesting that LOF variants m ay either act in a recessive manner or have a much milder effect than missense v ariants. In summary, while there is some suspicion for a pathogenic role in the heterozygous state, the clinical significance of the c.631-2A>G variant, with re gard to dominant ARVC is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PP3, PS3_Supporting.
GeneDx	RCV000181140	SCV000233417	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32466575, 25390934, 33684294, 32853555, 31402444, 32665702, 23812740, 31872082, 34135346, 33087929, 29788292, 33500567, 17186466)
Invitae	RCV000018344	SCV000950273	pathogenic	Arrhythmogenic right ventricular dysplasia 11	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 of the DSC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). This variant is present in population databases (rs397514042, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466). ClinVar contains an entry for this variant (Variation ID: 16850). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17186466). For these reasons, this variant has been classified as Pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000018344	SCV001251504	likely pathogenic	Arrhythmogenic right ventricular dysplasia 11		criteria provided, single submitter	research	This variant alters a canonical splice acceptor site in DSC2. This variant has been described previously in the heterozygous state in a patient with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466).
Color Diagnostics, LLC DBA Color Health	RCV001183801	SCV001349628	uncertain significance	Cardiomyopathy	2023-02-28	criteria provided, single submitter	clinical testing	This variant alters the canonical splice acceptor site in intron 5 of the DSC2 gene. Computational splicing tools predict that this variant may disrupt splicing. This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466, 23812740). This variant has also been identified in 4/251040 chromosomes in the general population by the Genome Aggregation Database (gnomAD), as well as in a supercentenarian (110 years or older) (PMID: 25390934). Quantitative real-time PCR in cardiac tissue biopsy of an affected individual has shown that this variant leads to aberrant splicing and reduced DSC2 protein levels (PMID: 17186466). Splice and other loss-of-function DSC2 variants have been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy. Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSC2 variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. Therefore, this variant is classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000018344	SCV002021763	pathogenic	Arrhythmogenic right ventricular dysplasia 11	2020-12-23	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000181140	SCV002502809	likely pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000018344	SCV003835899	likely pathogenic	Arrhythmogenic right ventricular dysplasia 11	2022-12-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003338383	SCV004058107	likely pathogenic	Cardiovascular phenotype	2023-09-08	criteria provided, single submitter	clinical testing	The c.631-2A>G intronic variant results from an A to G substitution two nucleotides before from coding exon 6 in the DSC2 gene. This variant has been detected in an individual from an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort with limited clinical detail, and in an individual reported to meet ARVC diagnostic criteria (Baskin B et al. Hum Genet, 2013 Nov;132:1245-52; Heuser A et al. Am J Hum Genet, 2006 Dec;79:1081-8). This variant has also been detected in several cohorts without known ARVC; however, clinical details were often limited (Mazzarotto F et al. Genet Med, 2021 05;23:856-864; Carruth ED et al. Circ Genom Precis Med, 2021 04;14:e003302; Lacaze P et al. NPJ Genom Med, 2021 Jun;6:51; van Rooij J et al. Genet Med, 2020 11;22:1812-1820; Roman TS et al. Am J Hum Genet, 2020 10;107:596-611; Gierman HJ et al. PLoS One, 2014 Nov;9:e112430). In RNA studies by one group, this alteration resulted in aberrant splicing due to use of a cryptic donor site resulting in a frameshift and premature truncation (Heuser A et al. Am J Hum Genet, 2006 Dec;79:1081-8). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
OMIM	RCV000018344	SCV000038623	pathogenic	Arrhythmogenic right ventricular dysplasia 11	2006-12-01	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000181140	SCV001952497	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000181140	SCV001972196	pathogenic	not provided		no assertion criteria provided	clinical testing