ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.46A>G (p.Ile16Val) (rs376660601)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489115 SCV000576795 uncertain significance not provided 2017-04-19 criteria provided, single submitter clinical testing The I16V variant has not been published as pathogenic or been reported as benign to our knowledge. It is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position where only amino acids with similar properties to isoleucine (I) are tolerated across species. However, the I16V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV001064778 SCV001229698 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-05-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 16 of the DSG2 protein (p.Ile16Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs376660601, ExAC 0.002%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 426374). 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 valine 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. 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.
Color Health, Inc RCV001184828 SCV001350905 uncertain significance Cardiomyopathy 2018-11-13 criteria provided, single submitter clinical testing

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