ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.578C>T (p.Thr193Met)

gnomAD frequency: 0.00001  dbSNP: rs1365721398
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000516563 SCV000612557 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001062071 SCV001226844 uncertain significance Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2019-03-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 193 of the CACNA1A protein (p.Thr193Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 446934). 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 disruptive, 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.
GeneDx RCV001755761 SCV001997139 uncertain significance not provided 2019-12-26 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in nearby residues reported in the Human Gene Mutation Database (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

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