ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.4322C>T (p.Thr1441Met) (rs727503835)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723807 SCV000202331 uncertain significance not provided 2014-01-13 criteria provided, single submitter clinical testing
GeneDx RCV000723807 SCV000619768 uncertain significance not provided 2017-08-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1C gene. The T1441M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant has been classified as a variant of uncertain significance by other clinical laboratories in ClinVar (SCV000202331.5, SCV000553020.1; Landrum et al., 2016). Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, the T1441M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1441M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals.
Invitae RCV000468006 SCV000553020 uncertain significance Long QT syndrome 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1441 of the CACNA1C protein (p.Thr1441Met). The threonine residue is moderately 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 CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 166773). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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.

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