Submissions for variant NM_000719.7(CACNA1C):c.5492C>T (p.Thr1831Met) (rs186015395)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000271609	SCV000377904	likely benign	Brugada syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000326769	SCV000377905	likely benign	Timothy syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000631690	SCV000752773	uncertain significance	Long QT syndrome	2018-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 1831 of the CACNA1C protein (p.Thr1831Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs186015395, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 308160). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine 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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