ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2270T>C (p.Met757Thr) (rs876657792)

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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 RCV000223557 SCV000271715 uncertain significance not specified 2015-05-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Met757Thr var iant in DSG2 has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. Methionine (Met) at position 757 is not conserved in evolution and 1 mammal (elephant) carries a threonine (Thr), raising the possibility that this change may be tolerated. In summary, while th e clinical significance of the p.Met757Thr variant is uncertain, the presence of the variant amino acid in other species suggests that it is more likely to be b enign.
Color Health, Inc RCV000771971 SCV000904925 uncertain significance Cardiomyopathy 2019-07-09 criteria provided, single submitter clinical testing
Invitae RCV000795727 SCV000935198 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-06-20 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 757 of the DSG2 protein (p.Met757Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 228631). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0. The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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