ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1912G>A (p.Gly638Arg) (rs201564919)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154703 SCV000204382 uncertain significance not specified 2016-11-07 criteria provided, single submitter clinical testing The p.Gly638Arg variant in DSG2 has been identified in 1 Caucasian individual wi th HCM (LMM data) and at least 1 Caucasian individual with ARVC/D (De Bortoli 2 010, Rigato 2013). Although the variant segregated with disease in one affected sibling, it was also identified in 2 apparently unaffected older siblings (De Bo rtoli 2010, Rigato 2013). This variant has been identified in 14/66666 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs201564919). Computational prediction tools and conservation analy sis suggest that the p.Gly638Arg variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. In summary, the cl inical significance of the p.Gly638Arg variant is uncertain.
GeneDx RCV000766866 SCV000233506 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing The G638R variant in the DSG2 gene has been reported in one Italian family in association with ARVC and it was not observed in 400 control chromosomes (De Bortoli et al., 2010). This study identified G638R in one individual with ARVC along with two other variants (N375I in the DSP gene and c.2687_2688insGA in the DSC2 gene). Since c.2687_2688insGA was seen in 1.5% of control chromosomes, the study reclassified this variant as likely benign (De Bortoli et al., 2010). Additional familial testing revealed G638R was present without N375I in two unaffected relatives and one individual who met diagnostic criteria for ARVC (De Bortoli et al., 2010). The G638R variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The G638R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In addition, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with ARVC. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000539539 SCV000641967 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 638 of the DSG2 protein (p.Gly638Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs201564919, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant was observed in affected and unaffected individuals from a family with arrhythmogenic right ventricular cardiomyopathy (PMID:20197793) and an individual that suffered a sudden unexplained death (PMID: 27930701). ClinVar contains an entry for this variant (Variation ID: 161224). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000619011 SCV000737779 uncertain significance Cardiovascular phenotype 2019-07-03 criteria provided, single submitter clinical testing The p.G638R variant (also known as c.1912G>A), located in coding exon 13 of the DSG2 gene, results from a G to A substitution at nucleotide position 1912. The glycine at codon 638 is replaced by arginine, an amino acid with dissimilar properties. This variant was seen in both affected and unaffected members of a single Italian family, who also had two other variants in genes associated with arrhythmogenic right ventricular cardiomyopathy (De Bortoli M et al. Eur. J. Hum. Genet., 2010 Jul;18:776-82). In addition, this variant was identified in a 24-year-old deceased female in conjunction with variants in the RYR2 and TTN genes (Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358). This variant has also been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. <br />
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170377 SCV001332952 uncertain significance Cardiomyopathy 2018-11-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV001170377 SCV001350806 uncertain significance Cardiomyopathy 2020-08-27 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 638 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Cardiomyocytes from a heterozygous carrier have shown ion channel dysfunctions and abnormal cellular electrophysiology as well as enhanced sensitivity to adrenergic stimulation (PMID: 29566126). This variant was reported in one individual affected with arrhythmogenic right ventricular cardiomyopathy and in three unaffected individuals from a family (PMID:20197793) and an individual affected with sudden death (PMID: 27930701). It has been shown that this variant segregates with disease in a family affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29566126). This variant has also been identified in 33/280710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CSER _CC_NCGL, University of Washington RCV000148474 SCV000190175 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000766866 SCV001740923 uncertain significance not provided no assertion criteria provided clinical testing

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