ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.631-2A>G (rs397514042)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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, 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 2018-09-19 criteria provided, single submitter clinical testing The c.631-2A>G variant in the DSC2 gene has been reported previously in a patient with ARVC (Heuser et al., 2006). The c.631-2A>G was also identified in an asymptomatic individual from a cohort of supercentenarians undergoing whole genome sequencing (Gierman et al., 2014). This splice site variant destroys the canonical splice acceptor site in intron 5 and is predicted to cause abnormal gene splicing (Heuser et al., 2006). This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.631-2A>G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.631-2A>G as a pathogenic variant.
Invitae RCV000018344 SCV000950273 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-09-06 criteria provided, single submitter clinical testing This sequence change affects acceptor splice site in intron 5 of the DSC2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs397514042, ExAC 0.002%). This variant has been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466, 23812740). ClinVar contains an entry for this variant (Variation ID: 16850). Experimental studies have shown that this change results in aberrant splicing, decreased mRNA expression, and zebrafish morpholinos containing this variant show significant cardiac defects (PMID: 17186466). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSC2 are known to be pathogenic (PMID: 18957847, 23863954, 23911551). 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 cardiomyopathy, type 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 RCV001183801 SCV001349628 uncertain significance Cardiomyopathy 2020-02-09 criteria provided, single submitter clinical testing
OMIM RCV000018344 SCV000038623 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 11 2006-12-01 no assertion criteria provided literature only

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