Submissions for variant NM_024422.6(DSC2):c.943-1G>A

gnomAD frequency: 0.00002  dbSNP: rs796756333

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484445	SCV000567827	likely pathogenic	not provided	2024-02-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21606396, 25525159, 25616645, 30847666, 31402444, 23871674, 34135346, 33662488, 35819174, 25820315)
Ambry Genetics	RCV000617404	SCV000736954	pathogenic	Cardiovascular phenotype	2023-01-27	criteria provided, single submitter	clinical testing	The c.943-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 8 of the DSC2 gene. This alteration has been reported in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Cox MG et al. Circulation, 2011 Jun;123:2690-700). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000601124	SCV000743495	pathogenic	Arrhythmogenic right ventricular dysplasia 11	2017-02-23	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000601124	SCV000744765	pathogenic	Arrhythmogenic right ventricular dysplasia 11	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184323	SCV001350275	uncertain significance	Cardiomyopathy	2022-04-05	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the canonical c.-1 position of the intron 7 splice acceptor site of the DSC2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. One of the possible molecular consequences of this variant is an in-frame skipping of exon 8, resulting in a mutant protein lacking 45 amino acids from the extracellular domain of the DSC2 protein. Alternatively, a downstream AG at c.953_954 may be utilized for splicing, resulting in a transcript missing the first 12 nucleotides (4 amino acids) from the beginning of exon 8. To our knowledge, functional RNA and protein studies have not been reported for this variant. This variant has been reported in at least one Dutch individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396, 23871674, 25820315, 30847666, 31386562) and in an asymptomatic family member of the proband (PMID: 21606396). This variant has also been observed in an asymptomatic Australian individual aged 70 years and older without a history of cardiovascular events (PMID: 34135346). 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	RCV000484445	SCV002502769	likely pathogenic	not provided	2021-10-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000484445	SCV004702249	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	DSC2: PM2, PS4:Moderate, PVS1:Moderate
All of Us Research Program, National Institutes of Health	RCV004806355	SCV005427486	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-03-24	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the canonical c.-1 position of the intron 7 splice acceptor site of the DSC2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. One of the possible molecular consequences of this variant is an in-frame skipping of exon 8, resulting in a mutant protein lacking 45 amino acids from the extracellular domain of the DSC2 protein. Alternatively, a downstream AG at c.953_954 may be utilized for splicing, resulting in a transcript missing the first 12 nucleotides (4 amino acids) from the beginning of exon 8. To our knowledge, functional RNA and protein studies have not been reported for this variant. This variant has been reported in at least one Dutch individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396, 23871674, 25820315, 30847666, 31386562) and in an asymptomatic family member of the proband (PMID: 21606396). This variant has also been observed in an asymptomatic Australian individual aged 70 years and older without a history of cardiovascular events (PMID: 34135346). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000601124	SCV005838809	pathogenic	Arrhythmogenic right ventricular dysplasia 11	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396, 31386562). ClinVar contains an entry for this variant (Variation ID: 419777). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000601124	SCV000733778	likely pathogenic	Arrhythmogenic right ventricular dysplasia 11		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000484445	SCV001925077	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000484445	SCV001956040	likely pathogenic	not provided		no assertion criteria provided	clinical testing