ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1114-316G>A (rs587782933)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170768 SCV000223323 pathogenic not provided 2017-04-11 criteria provided, single submitter clinical testing The G402S variant in the CACNA1C gene has been reported as a de novo disease-causing variant in a patient with Timothy syndrome, and was not reported in 364 healthy control alleles (Splawski I et al., 2005). The G402S variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, functional studies show that the G402S variant results in reduced calcium channel inactivation, increased calcium entry and maintained membrane depolarization, and therefore increased risk for arrhythmia (Splawski et al., 2005; Depil K et al., 2011; Gershon E et al., 2013). Moreover, the G402S mutation 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 across species (Splawski et al., 2005). In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant in a nearby residues (G406R) has been reported in association with Timothy syndrome, further supporting the functional importance of this region of the protein.In summary, G402S in the CACNA1C gene is interpreted as a disease-causing variant
Invitae RCV000805941 SCV000945916 pathogenic Long QT syndrome 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 402 of the CACNA1C protein (p.Gly402Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. The CACNA1C gene has multiple clinically relevant transcripts. The c.1204G>A variant occurs in alternate transcript NM_001129840.1, which corresponds to position c.1114-316G>A in NM_000719.6, the primary transcript listed in the Methods. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with atypical Timothy syndrome (TS2) including individuals where the variant arose de novo (PMID: 25691416, 24773605, 15863612, 23979604). ClinVar contains an entry for this variant (Variation ID: 155775). Experimental studies have shown that this missense change results in reduced CaV1.2 channel inactivation (PMID: 21685391, 15863612, 26822303). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000143870 SCV000188738 likely pathogenic Paroxysmal familial ventricular fibrillation 1 2013-11-20 no assertion criteria provided clinical testing

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