Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are reported mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 10 (ARVD; MIM#610193) and dilated cardiomyopathy 1BB (DCM; MIM#612877) (ClinVar, PMID: 23071725). (I) 0108 - This gene is associated with both recessive and dominant disease. It is commonly associated to dominant inheritance, however recessive has been reported in severe DCM patients (OMIM). (I) 0112 - The ARVD condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional R-X-R/K-R furin cleavage site (PMID: 23381804). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternate change to tryptophan (p.(Arg46Trp)) has previously been reported as pathogenic and likely pathogenic (ClinVar, PMID: 20400443, PMID: 29178656). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in multiple patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ClinVar, Cardiomyopathy Database, PMID: 16773573, PMID: 23381804). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in transfected cells showed increased binding, consistent with a gain of function effect (PMID: 23071725). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This missense variant replaces arginine with glutamine at codon 46 in the propeptide sequence domain of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Studies with tissue samples from carrier individuals and in vitro functional studies have shown that this variant interferes with the cleavage of the N-terminal propeptide that is required for normal protein maturation (PMID: 23071725, 23381804, 31845994). This variant has been reported in over ten unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 23381804, 30790397, 31542937, 31386562, 32268277, 33821670, 23381804, 31542937). It has been shown that this variant segregates with disease in at least six families (PMID: 23381804, 31542937). This variant has been identified in 1/280866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

The p.R46Q pathogenic mutation (also known as c.137G>A), located in coding exon 3 of the DSG2 gene, results from a G to A substitution at nucleotide position 137. The arginine at codon 46 is replaced by glutamine, an amino acid with highly similar properties. This variant (also referred to as p.R45Q, c.134G>A) was identified in one or more individuals with features consistent with arrhythmogenic right ventricular cardiomyopathy (ARVC) and segregated with disease in at least one family (Awad MM et al. Am J Hum Genet, 2006 Jul;79:136-42; Bhuiyan ZA et al. Circ Cardiovasc Genet, 2009 Oct;2:418-27; Rasmussen TB et al. Hum Mutat, 2013 May;34:697-705; Broendberg AK et al. Eur J Hum Genet, 2018 03;26:303-313; Kerkar A et al. Circ Genom Precis Med, 2019 10;12:452-454). This alteration is located in a highly conserved recognition motif (RQKR) for the endoproteolytic cleavage of an NH2-terminal propeptide sequence, required for activation of the desmoglein protein (Posthaus H et al. FEBS Lett, 2003 Feb;536:203-8). Studies have suggested disruption of this site may prevent proper post-translational processing, and have demonstrated the immature protein may still localize and incorporate into desmosomal junctions, although the physiological relevance of these findings is not yet clear (Awad MM et al. Am J Hum Genet, 2006 Jul;79:136-42; Gaertner A et al. PLoS One, 2012 Oct;7:e47097; Rasmussen 2013 Hum Mutat 2013 May;34(5):697-705; Vite A et al. Europace, 2020 02;22:320-329). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

proposed classification - variant undergoing re-assessment, contact laboratory

ACMG codes:PS3,PS4M,PM2,PP3,PP5,

This missense variant replaces arginine with glutamine at codon 46 in the propeptide sequence domain of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Studies with tissue samples from carrier individuals and transfected cell lines have shown that this variant prevents the cleavage of the N-terminal propeptide that is required for normal protein maturation (PMID: 23071725, 23381804, 31845994). This variant has been reported in over ten unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 23381804, 30790397, 31542937, 31386562, 32268277, 33821670, 23381804, 31542937). It has been shown that this variant segregates with disease in at least six families (PMID: 23381804, 31542937). This variant has been identified in 1/280866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

This c.137G>A (p.Arg46Gln) variant in the DSG2 gene is reported in multiple probands affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID 16773573, 20031616, 20031617, 20400443, 21606390, 21606396, 23381804) and segregates with disease in some of the families (PMID 23071725, 23381804). Functional studies showed this is a potential gain-of-function variant which produces a mutant protein product with extended N-terminus (PMID 23381804). In addition, this variant is predicted to be damaging by multiple in silico algorithms. Therefore, the c.137G>A (p.Arg46Gln) variant in the DSG2 gene is classified as pathogenic.

Reported in ClinVar as pathogenic (ClinVar Variant ID#16812; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution has been shown to impair prodomain cleavage and occurs at a position that is conserved across species (Gaertner et al., 2012); This variant is associated with the following publications: (PMID: 28097316, 23911551, 20857253, 23137101, 26688388, 24967631, 21606396, 16773573, 20400443, 21606390, 20031616, 20031617, 29343803, 31542937, 31386562, 31402444, 30790397, 33019804, 31845994, 23071725, 23381804, 26582918)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the DSG2 protein (p.Arg46Gln). This variant is present in population databases (rs121913008, gnomAD 0.004%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 16773573, 23381804, 30790397, 31542937). It has also been observed to segregate with disease in related individuals. This variant is also known as 134G>A (R45Q). ClinVar contains an entry for this variant (Variation ID: 16812). Invitae Evidence 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 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. Experimental studies have shown that this missense change affects DSG2 function (PMID: 23071725). For these reasons, this variant has been classified as Pathogenic.