ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.137G>A (p.Arg46Gln) (rs121913008)

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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 RCV000211714 SCV000060921 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2017-02-01 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000181197 SCV000233475 pathogenic not provided 2018-07-31 criteria provided, single submitter clinical testing The R46Q pathogenic variant in the DSG2 gene has previously been reported in several individuals diagnosed with ARVC (Awad et al., 2006; Bhuiyan et al., 2009; Fressart et al., 2010; Quarta et al., 2011; Rasmussen et al., 2013). Awad et al. (2006) first reported the R46Q variant (reported as R45Q) in one individual who met the diagnostic Task Force Criteria for ARVC (Awad et al., 2006). The R46Q variant was subsequently reported in two unrelated individuals of Dutch ancestry that were then found to have the same haplotype, suggesting R46Q may represent a founder mutation in the Dutch population (Bhuiyan et al., 2009). Fressart et al. (2010) has also identified the R46Q variant in three individuals diagnosed with ARVC, with one of these individuals also harboring a PKP2 gene variant. Rasmussen et al. (2013) reported this variant in seven index patients with ARVC, three of which harbored a second variant in a desmosomal gene, however, this variant segregated independently with disease in three relatives. Additionally, the R46Q variant is not observed at a significant frequency in large populations cohorts (Lek et al., 2016). The R46Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution has been shown to impair prodomain cleavage and occurs at a position that is conserved across species (Gaertner et al., 2012).
OMIM RCV000018305 SCV000038584 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2006-07-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University 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 ( (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).

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