Total submissions: 19
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Human Genetics, |
RCV000018305 | SCV007541014 | pathogenic | Arrhythmogenic right ventricular dysplasia 10 | 2022-02-08 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000018305 | SCV005398219 | pathogenic | Arrhythmogenic right ventricular dysplasia 10 | 2022-02-02 | criteria provided, single submitter | clinical testing | 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 |
| All of Us Research Program, |
RCV000211714 | SCV004830224 | pathogenic | Arrhythmogenic right ventricular cardiomyopathy | 2024-06-09 | criteria provided, single submitter | clinical testing | 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. |
| Color Diagnostics, |
RCV001798008 | SCV004363155 | pathogenic | Cardiomyopathy | 2024-03-26 | criteria provided, single submitter | clinical testing | 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. |
| Fulgent Genetics, |
RCV002482885 | SCV002781170 | pathogenic | Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB | 2021-07-20 | criteria provided, single submitter | clinical testing | |
| Genetics and Molecular Pathology, |
RCV000018305 | SCV002761732 | pathogenic | Arrhythmogenic right ventricular dysplasia 10 | 2022-03-09 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002381255 | SCV002699804 | pathogenic | Cardiovascular phenotype | 2025-07-09 | criteria provided, single submitter | clinical testing | 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. |
| CHEO Genetics Diagnostic Laboratory, |
RCV001798008 | SCV002043138 | likely pathogenic | Cardiomyopathy | 2019-10-30 | criteria provided, single submitter | clinical testing | |
| Hudson |
RCV000018305 | SCV001870339 | pathogenic | Arrhythmogenic right ventricular dysplasia 10 | 2020-12-16 | criteria provided, single submitter | research | ACMG codes:PS3,PS4M,PM2,PP3,PP5, |
| Labcorp Genetics |
RCV000018305 | SCV001579553 | pathogenic | Arrhythmogenic right ventricular dysplasia 10 | 2026-01-05 | criteria provided, single submitter | clinical testing | 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. |
| Human Genome Sequencing Center Clinical Lab, |
RCV000018305 | SCV001435002 | pathogenic | Arrhythmogenic right ventricular dysplasia 10 | 2019-02-05 | criteria provided, single submitter | clinical testing | 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. |
| Gene |
RCV000181197 | SCV000233475 | pathogenic | not provided | 2021-10-21 | criteria provided, single submitter | clinical testing | 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) |
| Laboratory for Molecular Medicine, |
RCV000211714 | SCV000060921 | pathogenic | Arrhythmogenic right ventricular cardiomyopathy | 2017-02-01 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000181197 | SCV002038024 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics, |
RCV000181197 | SCV002034413 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000181197 | SCV001951223 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Genome Diagnostics Laboratory, |
RCV000181197 | SCV001931420 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000181197 | SCV000280082 | likely pathogenic | not provided | 2014-02-06 | no assertion criteria provided | clinical testing | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify this variant as likely disease causing. This variant has been reported in 6 unrelated individuals with ARVC (7 total, though two shared a haplotype) (Awad et al 2006, Bhuiyan et al 2009 and Fressart et al 2010). There is minimal segregation data on the variant. Awad et al (2006) first reported the variant (as p.Arg45Gln) in an individual with ARVC. The proband’s mother had this variant and was thought to be an obligate carrier as her father’s history was suspicious for ARVC. While this study did not include analysis of other ARVC genes, the same group later reported on evaluated of 5 genes in their cohort, including the individuals originally reported in the 2006 paper (den Haan et al 2009). From that paper it seems that this patient had only the one desmosomal variant, though it isn’t completely clear that the individual with this variant reported by Awad et al is the same as the individual reported by den Haan et al. Bhuiyan et al (2009) reported the variant in two unrelated individuals in their Dutch cohort who had the same haplotype. These patients did not have any variants in PKP2 or DSC2. Fressart et al (2010) reported three unrelated ARVC patients with this variant. Two of these patients had no other variants in JUP, DSP, PKP2, DSG2, and DSC2. The third patient also had a missense variant in PKP2 (p.Arg811Ser) that was absent in the 300 controls reported in the paper but is present in one of ~2500 individuals in the NHLBI Exome dataset. Quarta et al (2011) reported observing the variant in their British sample (few details provided). This is a semi conservative amino acid change with a basic Arginine replaced with a neutral Glutamine. Argninie is highly conserved at this amino acid position across species. Awad et al (2006) reported that this variant affects a residue that is a recognition site for cleavage of the protein precursor, suggesting that the variant will impede production of a mature protein product. Gaertner et al (2012) expressed the extracellular cadherin domain of the desmoglein 2 protein with p.Arg46Gln and found that the variant destroyed a prodomain cleavage site leading to failed cleavage in vitro. They also observed increased cellular adhesion. In silico analysis with PolyPhen predicts the amino acid change to be probably damaging to protein structure/function. Other missense variants at or near this codon have been reported in ARVC cases and are not present in the current NHLBI Exome dataset (Nov 2011, ~2500 individuals): p.Arg46Trp (Fressart et al 2010), p.Arg49His (Fressart et al 2010, Awad et al 2006, den Haan et al 2009, Barahona-Dussault et al 2010). In total this variant has not been seen in 7,850 published controls, laboratory controls, and publicly available general population samples. Across all publications it has not been observed in over 1150 presumably healthy controls. p.Arg46Gln is not listed in1000 Genomes (http://browser.1000genomes.org/index.htm) (as of 2/6/14). It is listed in dbSNP, but that points to the OMIM entry for the variant seen in patients with ARVC. There is no variation at codon 46 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 2/6/14). |
| OMIM | RCV000018305 | SCV000038584 | pathogenic | Arrhythmogenic right ventricular dysplasia 10 | 2006-07-01 | no assertion criteria provided | literature only |