ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.3233G>C (p.Gly1078Ala) (rs1064795829)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000757181 SCV000572009 uncertain significance not provided 2016-10-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSG2 gene. The G1078A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G1078A variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the G1078A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and this substitution occurs at a position that is not conserved across species. Lastly, in silico analysis predicts this variant likely does not alter the protein structure/function.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757181 SCV000885317 uncertain significance not provided 2018-05-04 criteria provided, single submitter clinical testing The DSG2 c.3233G>C; p.Gly1078Ala variant (ClinVar variant ID 422516), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.0004% (identified on 1 out of 246,030 chromosomes). The glycine at position 1078 is weakly conserved, considering 12 species, and computational analyses of the effects of the p.Gly1078Ala variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Gly1078Ala variant cannot be determined with certainty.
Invitae RCV001241693 SCV001414728 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-04-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 1078 of the DSG2 protein (p.Gly1078Ala). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and alanine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 422516). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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