ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.202G>A (p.Ala68Thr) (rs752000790)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000761812 SCV000892013 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000357698 SCV000805139 uncertain significance Timothy syndrome 2018-01-31 criteria provided, single submitter clinical testing
GeneDx RCV000761812 SCV000223403 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing p.Ala68Thr (GCT>ACT): c.202 G>A in exon 2 of the CACNA1C gene (NM_000719.6). The A68T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A68T variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A68T 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. However, this substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. No missense mutations in nearby residues have been reported in association with LQTS, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in LQT panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000357698 SCV000377588 uncertain significance Timothy syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000262517 SCV000377589 uncertain significance Brugada syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781192 SCV000919075 likely benign not specified 2017-11-06 criteria provided, single submitter clinical testing Variant summary: The CACNA1C c.202G>A (p.Ala68Thr) variant involves the alteration of a conserved nucleotide and 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured here due to low reliability index and p-value, respectively). This variant was found in 41/261782 control chromosomes at a frequency of 0.0001566, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000309 (37/119594). This frequency is about 31 times the estimated maximal expected allele frequency of a pathogenic CACNA1C variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in multiple affected individuals without strong evidence for casualty. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without evidence for independent evaluation. Taken together, this variant is classified as likely benign.
Invitae RCV000794589 SCV000934007 uncertain significance Long QT syndrome 2018-08-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 68 of the CACNA1C protein (p.Ala68Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs752000790, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 27231019) and in an individual with primary electrical disease (PMID: 28341588). ClinVar contains an entry for this variant (Variation ID: 190709). 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. 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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