ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1880-2A>G (rs397514038)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211716 SCV000060933 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2010-12-17 criteria provided, single submitter clinical testing The 1880-2A>G variant has been reported in two siblings with ARVC and was absent from 560 matched control chromosomes, supporting a pathogenic role. However, b oth siblings also carried a second, possibly disease causing variant on the othe r copy of the DSG2 gene (Pilichou, 2006). RNA studies demonstrated that the 1880 -2A>G abolishes the splice site, leading to the use of a cryptic splice site 38 bp downstream. The aberrantly spliced mRNA was shown to lack the first 38 bp of exon 13, which is predicted to cause a frameshift starting at position 627 and p remature termination 19 amino acids later, leading to a truncated or absent prot ein (Pilichou, 2006). In summary, the severity of the change as well as absence from controls suggest that this variant is likely pathogenic.
GeneDx RCV000181225 SCV000233504 pathogenic not provided 2014-07-21 criteria provided, single submitter clinical testing c.1880-2 A>G: IVS12-2 A>G in intron 12 of the DSG2 gene (NM_001943.3). The c.1880-2 A>G mutation in the DSG2 gene has been reported previously in association with ARVC (Pilichou K et al., 2006). Pilichou et al. (2006) identified c.1880-2 A>G (reported as c.1881-2 A>G due to alternate nomenclature) in an individual with ARVC who also harbors a missense variant in the DSG2 gene. Segregation analysis in this individual's family suggest that c.1880-2 A>G is co-segregating independently with disease (Pilichou et al 2006). Furthermore, the c.1880-2 A>G mutation was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation destroys the canonical splice acceptor site in intron 12 and is predicted to cause abnormal gene splicing. Moreover, other splice site mutations in the DSG2 gene have been reported in association with ARVC. In summary, c.1880-2 A>G in the DSG2 gene is interpreted as a disease-causing mutation. The variant is found in ARVC panel(s).
Invitae RCV000018310 SCV000814564 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-06-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 12 of the DSG2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in heterozygosis in an individual affected with right ventricular cardiomyopathy and in compound heterozygosis (in trans) with rare missense varaint in two siblings affected with ARVC (PMID: 16505173, 27532257). This variant is also known as c.1881-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 16817). Experimental studies have shown that this intronic change leads to the inactivation of the natural intron 12 donor splice site and to the activation of a cryptic splice site in exon 13 that results in a transcript susceptible to NMD (PMID: 16505173). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSG2 are known to be pathogenic (PMID: 23381804, 23911551). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018310 SCV000038589 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2006-03-07 no assertion criteria provided literature only

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