ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1397C>T (p.Thr466Ile) (rs769137357)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485460 SCV000571941 uncertain significance not provided 2016-10-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSG2 gene. The T466I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This 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 T466I 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. However, this substitution occurs at a position that is not conserved across species and where Isoleucine is the wild type the opossum. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000642322 SCV000763991 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2017-11-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 466 of the DSG2 protein (p.Thr466Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs769137357, ExAC 0.01%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 422458). 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 isoleucine 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171306 SCV001334034 uncertain significance Cardiomyopathy 2018-05-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV001171306 SCV001351115 uncertain significance Cardiomyopathy 2019-10-09 criteria provided, single submitter clinical testing

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