ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.3386C>T (p.Thr1129Met)

gnomAD frequency: 0.00003  dbSNP: rs374549078
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002030253 SCV002270986 uncertain significance Long QT syndrome 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1129 of the CACNA1C protein (p.Thr1129Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 1484843). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV002458934 SCV002618234 uncertain significance Cardiovascular phenotype 2022-12-14 criteria provided, single submitter clinical testing The p.T1129M variant (also known as c.3386C>T), located in coding exon 27 of the CACNA1C gene, results from a C to T substitution at nucleotide position 3386. The threonine at codon 1129 is replaced by methionine, an amino acid with similar properties. According to data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, the association of this alteration with CACNA1C-related neurodevelopmental disorder is unknown; however, the association with CACNA1C-related Timothy syndrome or long QT syndrome is unlikely.

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