ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.151T>C (p.Trp51Arg) (rs1064794367)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486494 SCV000568967 uncertain significance not provided 2015-12-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSG2 gene. The W51R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The W51R variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W51R 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, missense variants in nearby residues (R46W, R46Q, R49H) have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014).
Invitae RCV001364103 SCV001560236 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-02-14 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 51 of the DSG2 protein (p.Trp51Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 420241). 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. 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000486494 SCV000924771 uncertain significance not provided 2016-05-17 no assertion criteria provided provider interpretation Given a lack of case data we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant is novel. We have seen the variant in one case of ARVC. Testing was done at GeneDx. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.998). The Trp at codon 51 is conserved in mammals and chicken. Other variants have been reported in association with disease at nearby codons (46 and 49). Kapplinger et al., 2011 report a “hot spot” for DSG2 variants between amino acids 24-388 in patients with ARVC but not in controls. Of note, Kapplinger et al. (2011) from Michael Ackerman’s group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants—similar to the 21% yield in 175 Dutch and U.S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with caution. There is no variation at codon 51 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 5/17/16). Coverage is 25-30x in over 95% of people, with mean coverage at 80x at this position (18-29099835-T-C).

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