ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2434G>A (p.Gly812Ser) (rs121913010)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181231 SCV000233510 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSG2 gene. The G812S variant has been previously reported in individuals with ARVC (Gehmlich et al., 2010; Walsh et al., 2017). Gehmlich et al. (2010) also showed that in one family, G812S segregated with ARVC in three affected relatives of the proband; however, G812S was not detected in one relative with borderline ARVC. The G812S variant has also been observed in one other individual referred for cardiomyopathy genetic testing at GeneDx, although this individual harbored additional cardiogenetic variants and no segregation data are available to further clarify the role of this variant in disease. Additionally, this variant has been reported as a secondary finding in two individuals referred for whole exome or genome sequencing (Retterer et al., 2016; Stavropoulos et al., 2016), and has been observed at a global allele frequency of 10/277052 (0.004%) alleles in large population cohorts, including 3/34420 (0.009%) alleles from individuals of Latino ancestry (Lek et al., 2016).The G812S 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, in vitro binding assays and expression studies in mammalian cells have thus far shown that G812S does not impact the binding properties or cellular localization of desmoglein-2 protein (Gehmlich et al., 2010; Schlipp et al., 2014). Furthermore, although another missense variant at the same residue (G812C) has been reported in the DSG2 gene in association with ARVC (Awad et al., 2006), the clinical significance of this variant also remains to be definitively determined.
Invitae RCV000456354 SCV000551019 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 812 of the DSG2 protein (p.Gly812Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs121913010, ExAC 0.003%). This variant has been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy/dysplasia (PMID: 20708101, 27532257, 28454995). ClinVar contains an entry for this variant (Variation ID: 199817). Experimental studies have shown that this missense change does not affect cardiomyocyte cohesion in vitro, but the clinical relevance of this observation is uncertain (PMID: 25213555). Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, 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 RCV000620437 SCV000737554 uncertain significance Cardiovascular phenotype 2019-03-20 criteria provided, single submitter clinical testing The p.G812S variant (also known as c.2434G>A), located in coding exon 15 of the DSG2 gene, results from a G to A substitution at nucleotide position 2434. The glycine at codon 812 is replaced by serine, an amino acid with similar properties. This alteration has been reported in several arrhythmogenic right ventricular cardiomyopathy (ARVC) patients and in a stillbirth cohort, but it has also been detected in multiple individuals without significant ARVC findings (Gehmlich K et al. Heart Rhythm, 2010 Oct;7:1446-53; Retterer K et al. Genet. Med., 2016 07;18:696-704; Stavropoulos DJ et al. NPJ Genom Med, 2016 Jan;1:; Walsh R et al. Genet. Med., 2017 02;19:192-203; Sahlin E et al. PLoS ONE, 2019 Jan;14:e0210017; Ambry internal data; GeneDx pers. comm.; Invitae pers. comm.). This alteration was reported to segregate with disease in four individuals from a single family with ARVC; however, one young relative with a borderline ARVC diagnosis was negative for this variant (Gehmlich K et al, Heart Rhythm 2010 Oct; 7(10):1446-53). In vitro functional studies have not detected a negative impact on DSG2 function; however, these studies may not reflect in vivo function (Gehmlich K et al, Heart Rhythm 2010 Oct; 7(10):1446-53; Schlipp A et al. Cardiovasc. Res., 2014 Nov;104:245-5). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000181231 SCV001151515 likely pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV001182503 SCV001347969 uncertain significance Cardiomyopathy 2019-06-26 criteria provided, single submitter clinical testing

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