ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.959C>T (p.Thr320Met) (rs377737331)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482096 SCV000566212 uncertain significance not provided 2016-10-20 criteria provided, single submitter clinical testing The T320M variant of uncertain significance in the CACNA1C gene has not been published as a pathogenic variant,nor has it been reported as a benign variant to our knowledge. T320M was not observed with any significantfrequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, nor was it observed with any significant frequency in the Exome Aggregation Consortium(ExAC) data set. Although, this substitution occurs at a position that is not conserved, the T320M variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differin polarity, charge, size and/or other properties. Moreover, in silico analysis predicts this variant is probablydamaging to the protein structure/function. Nevertheless, no pathogenic missense variants in nearby residues havebeen reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene isnot known to harbor disease-causing variants.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000814196 SCV000954597 uncertain significance Long QT syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 320 of the CACNA1C protein (p.Thr320Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs377737331, ExAC 0.01%). This variant has been reported in an individual who suffered an unexplained cardiac arrest (PMID: 28600387). ClinVar contains an entry for this variant (Variation ID: 418848). 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: "Deleterious"; PolyPhen-2: "Benign"; 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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