ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.523+2T>C (rs397516709)

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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 RCV000037309 SCV000060966 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2018-02-21 criteria provided, single submitter clinical testing The c.523+2T>C variant in DSG2 has been reported in 6 individuals with clinical features of arrhythmogenic right ventricular cardiomyopathy (ARVC; Fressart 2010 , Tan 2010, LMM unpublished data). This variant has been identified in 2/105830 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b; dbSNP rs397516709) and reported in ClinVar (Variation ID 4432 1). c.523+2T>C variant occurs in the invariant region (+/- 1,2) of the splice co nsensus sequence and is predicted to cause altered splicing leading to an abnorm al or absent protein. Heterozygous loss of function of the DSG2 gene has been im plicated in ARVC. In summary, although additional studies are required to fully establish its clinical significance, the c.523+2T>C variant is likely pathogenic . ACMG/AMP Criteria applied: PM2; PVS1_Moderate; PS4_Moderate.
GeneDx RCV000181206 SCV000233484 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing The c.523+2 T>C variant has been reported in multiple unrelated individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Fressart et al., 2010; Tan et al., 2010). The c.523+2 T>C variant was not observed in approximately 5,900 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 variant destroys the canonical splice donor site in intron 5 and is predicted to cause abnormal gene splicing. Other splice site variants in the DSG2 gene have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). In summary, c.523+2 T>C in the DSG2 gene is interpreted as a pathogenic variant. However, other genetic and environmental factors influence disease expression and severity, and some carriers may never become symptomatic. The variant is found in ARVC panel(s).
Invitae RCV000232524 SCV000287244 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-03-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 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 individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 2040044, 20857253). 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.
Ambry Genetics RCV000241644 SCV000320191 pathogenic Cardiovascular phenotype 2020-06-15 criteria provided, single submitter clinical testing The c.523+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 5 of the DSG2 gene. This alteration has been previously reported in several patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), sometimes in conjunction with other ARVC variants (Fressart V, Europace 2010 Jun; 12(6):861-8; Tan BY, J Cardiovasc Transl Res 2010 Dec; 3(6):663-73). This variant has also been detected in a sudden infant death syndrome cohort (Tester DJ et al. J. Am. Coll. Cardiol., 2018 03;71:1217-1227). 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 a disease-causing mutation.

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