ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1499T>C (p.Ile500Thr)

gnomAD frequency: 0.00001  dbSNP: rs769741655
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001179231 SCV001343842 uncertain significance Cardiomyopathy 2023-03-09 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 500 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSG2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002393397 SCV002701325 uncertain significance Cardiovascular phenotype 2022-01-05 criteria provided, single submitter clinical testing The p.I500T variant (also known as c.1499T>C), located in coding exon 11 of the DSG2 gene, results from a T to C substitution at nucleotide position 1499. The isoleucine at codon 500 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV002559760 SCV003448993 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2021-12-12 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 500 of the DSG2 protein (p.Ile500Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 920473). 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 threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function.
All of Us Research Program, National Institutes of Health RCV004006546 SCV004819549 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 500 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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