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

dbSNP: rs121913006

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2020-12-17	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Functional studies show R49H abolishes pro-peptide cleavage and affects desmosomal adhesiveness (Vite et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29237690, 23671136, 19151369, 20152563, 16773573, 20400443, 27532257, 28283360, 19863551, 25820315, 20031617, 20857253, 31447099, 31845994, 32268277, 31645976, 30790397, 32356610, 31402444)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000018303	SCV000839951	pathogenic	Arrhythmogenic right ventricular dysplasia 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000018303	SCV002224220	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2023-05-17	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. ClinVar contains an entry for this variant (Variation ID: 16810). This variant is also known as R48H. This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 19151369, 19863551, 20400443). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs121913006, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 49 of the DSG2 protein (p.Arg49His). For these reasons, this variant has been classified as Pathogenic.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV002254518	SCV002522687	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2022-06-03	criteria provided, single submitter	clinical testing	We observed a rare c.146G>A (p.R49H) genetic variant in the DSG2 gene in a 19-y.o. male proband, diagnosed with arrhythmogenic right ventricular cardiomyopathy (definite diagnosis). ClinVar contains an entry for this variant (Variation ID: 16810) observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 16773573‚ 19151369‚ 20152563‚ 20400443‚ 19863551‚ 20031617‚ 23671136‚ 28283360‚ 25820315‚ 20857253). Online bioinformatic resources classify the c.146G>A (p.R49H) variant as probably pathogenic. The p.R49H variant predicted to abolish a cleavage motif Arg-X-Lys-Arg (RXKR) in desmoglein, disrupting production of mature, functional protein (Awad et al., 2006). Functional studies show the c.146G>A (p.R49H) variant abolishes pro-peptide cleavage and affects desmosomal adhesiveness (Vite et al., 2020). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000211715	SCV004822556	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-12-11	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 p.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 dysplasia 10	2006-07-01	no assertion criteria provided	literature only