ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs727502989
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 dysplasia 10 2022-09-29 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 751 of the DSG2 protein (p.Thr751Ile). This variant is present in population databases (rs727502989, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 163216). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function. 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 Diagnostics, LLC DBA Color Health RCV001183804 SCV001349631 uncertain significance Cardiomyopathy 2023-10-23 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 (PMID: 26220970). 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.
Fulgent Genetics, Fulgent Genetics RCV002483303 SCV002782966 uncertain significance Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB 2021-10-31 criteria provided, single submitter clinical testing

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