ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2212G>A (p.Ala738Thr) (rs397516705)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037283 SCV000060940 uncertain significance not specified 2011-01-05 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ala738Thr varia nt has not been reported in the literature nor has it been detected in any other family tested by our laboratory. Alanine (Ala) at position 738 is not conserved across closely related species and one species (mouse) naturally carries the mu tant amino acid, reducing the likelihood that the change is pathogenic. In addit ion, this variant has not been seen in isolation in an affected individual and a dditional data is therefore needed to further assess its impact when present in isolation. In summary, this variant is less likely to be pathogenic but this can not be determined with certainty at this point.
Invitae RCV001056749 SCV001221211 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 738 of the DSG2 protein (p.Ala738Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs397516705, ExAC 0.006%). This variant has not been reported in the literature in individuals with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 44298). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Color Health, Inc RCV001189712 SCV001357062 uncertain significance Cardiomyopathy 2020-06-30 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 738 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 been identified in 4/249418 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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