ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.146G>A (p.Arg49His) (rs121913006)

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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 RCV000211715 SCV000060922 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2019-01-31 criteria provided, single submitter clinical testing The p.Arg49His variant in DSG2 has been reported in > 10 individuals with clinical features of ARVC, including 1 de novo and 2 compound heterozygous occurrences (Awad 2006, den Haan 2009, Gandjbakhch 2009, Fressart 2010, Barahona-Dussault 2010, Tan 2010, Xu 2010, Gaido 2017, Walsh 2017). Additionally, the variant segregated with disease in 2 affected relatives from 1 family (Gaido, 2017). This variant has also been reported in ClinVar (Variation ID 16810) and has been identified in 1/113204 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that the p.Arg49His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg49His variant is likely pathogenic. ACMG/ AMP Criteria applied: PS2, PM2, PS4_Moderate, PP3.
GeneDx RCV000181198 SCV000233476 pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing The R49H pathogenic variant in the DSG2 gene has been published multiple times in association with ARVC (Awad et al., 2006; den Haan et al., 2009; Gandjbakhch et al., 2009; Barahona-Dussault et al., 2010; Fressart et al., 2010; Xu et al., 2010; Gaido et al., 2017). In addition, R49H was confirmed to be de novo in one male proband with sporadic ARVC (Gandjbakhch et al., 2009) and was reported to segregate with variable clinical presentations of ARVC among three adult males in the same family (Gaido et al., 2017). Furthermore, R49H is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Although R49H results in a conservative amino acid substitution, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Specifically, R49H is predicted to abolish a cleavage site in desmoglein, disrupting production of mature, functional protein (Awad et al., 2006). Moreover, variants in the same (R49C) and nearby residues (R46W, R46Q, W51S) have been reported in HGMD in association with ARVC, further supporting the functional importance of this residue and region of the protein.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000018303 SCV000839951 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2017-06-06 criteria provided, single submitter clinical testing This c.146G>A (p.Arg49His) variant in the DSG2 gene has previously been reported in a 41 y/o patient with ARVD cardiomyopathy [PMID 19151369]. Both parents were negative for the change, suggesting that this variant arises de novo in the patient. This variant was also reported in a 42 y/o patient with ARVD cardiomyopathy (reported as p.Arg48His in PMID 16773573]. The patient was compound heterozygous for p.Trp305* and p.Arg48His. The trp305* was inherited from the asymptomatic mother and also present in one sibling, also asymptomatic. The father was not available for testing. The variant is located in the propeptide domain, in the furin cleavage site and is hypothesized to disrupt the production of the mature protein. This variant has been observed in one heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/18-29099830-G-A). Arginine at position 49 of the DSG2 protein is highly conserved. While not clinically validated, computer-based algorithms SIFT and Polyphen2 predict this p.Arg49His change to be deleterious. It is thus interpreted as a pathogenic variant.
OMIM RCV000018303 SCV000038582 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2006-07-01 no assertion criteria provided literature only

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