ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.424C>A (p.Pro142Thr) (rs1005230453)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757180 SCV000885316 uncertain significance not provided 2018-03-20 criteria provided, single submitter clinical testing The DSG2 c.424C>A; p.Pro142Thr variant (rs1005230453), 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 245,956 chromosomes). The proline at position 142 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Pro142Thr variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on the available information, the clinical significance of the p.Pro142Thr variant cannot be determined with certainty.
Invitae RCV000823895 SCV000964766 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 142 of the DSG2 protein (p.Pro142Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with arrhythmogenic right ventricular cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 618608). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV001181910 SCV001347155 uncertain significance Cardiomyopathy 2021-02-19 criteria provided, single submitter clinical testing This missense variant replaces proline with threonine at codon 142 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 1/249318 chromosomes 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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