ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2252C>T (p.Thr751Ile) (rs727502989)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150542 SCV000197765 uncertain significance not specified 2014-11-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr751Ile var iant in DSG2 has not been previously reported in individuals with cardiomyopathy , but has been identified in 2/67482 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org). Threonine (Thr) at positio n 751 is poorly conserved in evolution and one mammalian species (megabat) carri es an isoleucine (Ile) at this position, raising the possibility that this chang e may be tolerated. Computational prediction tools also suggest that this varian t may not impact the protein, though this information is not predictive enough t o rule out pathogenicity. In summary, while the clinical significance of the p.T hr751Ile variant is uncertain, these data suggest that it is more likely to be b enign.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000238657 SCV000297109 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-10-16 criteria provided, single submitter clinical testing
Invitae RCV000802216 SCV000942037 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-10-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 751 of the DSG2 protein (p.Thr751Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs727502989, ExAC 0.003%). This variant has not been reported in the literature in individuals with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 163216). 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: Deleterious; PolyPhen-2: Benign; 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 RCV001183804 SCV001349631 uncertain significance Cardiomyopathy 2020-09-29 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 751 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 been reported in an individual affected with Brugada syndrome (Pietrelli 2014). This variant has been identified in 4/279340 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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