ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.523+1G>C

dbSNP: rs553299589
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798603 SCV002043148 likely pathogenic Cardiomyopathy 2020-03-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001850381 SCV002282694 pathogenic Arrhythmogenic right ventricular dysplasia 10 2022-11-01 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 188450). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257, 30790397; Invitae). This variant is present in population databases (rs553299589, gnomAD 0.01%). This sequence change affects a donor splice site in intron 5 of the DSG2 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 DSG2 are known to be pathogenic (PMID: 17105751, 31386562).
Ambry Genetics RCV002336383 SCV002640863 likely pathogenic Cardiovascular phenotype 2024-04-05 criteria provided, single submitter clinical testing The c.523+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 5 of the DSG2 gene. This variant has been reported in an individual indicated as having arrhythmogenic right ventricular cardiomyopathy, but clinical details were limited (Bourfiss M et al. Circ Genom Precis Med, 2022 Dec;15:e003704). Another alteration affecting this nucleotide (c.523+1G>A) was detected in a cohort referred for arrhythmogenic right ventricular cardiomyopathy (ARVC) genetic testing, and was also detected in a sudden cardiac arrest cohort (Walsh R et al. Genet. Med., 2017 02;19:192-203; Mellor G et al. Circ Cardiovasc Genet, 2017;10:e001686). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. 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.
Donald Williams Parsons Laboratory, Baylor College of Medicine RCV000505605 SCV000599976 pathogenic Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB 2014-09-17 no assertion criteria provided research This splice site variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was an incidental finding in our study, in a 4-year-old female with mixed neuroglial tumor.

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