ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.98A>G (p.Asn33Ser) (rs535608443)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170817 SCV000223372 uncertain significance not provided 2013-02-18 criteria provided, single submitter clinical testing p.Asn33Ser (AAT>AGT): c.98 A>G in exon 2 of the CACNA1C gene (NM_000719.6). The Asn33Ser variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asn33Ser results in a conservative amino acid substitution of one neutral, polar amino acid for another at a position that is not conserved across species. Consequently, in silico analysis predicts Asn33Ser is benign to the protein structure/function. However, one nearby mutation (Asn39Val) has been reported in association with Brugada syndrome (Antzeltevich C et al., 2007). In addition, the Asn33Ser 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. With the clinical and molecular information available at this time, we cannot definitively determine if Asn33Ser is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Fulgent Genetics,Fulgent Genetics RCV000765083 SCV000896288 uncertain significance Timothy syndrome; Brugada syndrome 3 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000170817 SCV001148517 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
Invitae RCV001036246 SCV001199598 uncertain significance Long QT syndrome 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 33 of the CACNA1C protein (p.Asn33Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 190679). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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