ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.2258C>T (p.Ala753Val)

gnomAD frequency: 0.00001  dbSNP: rs200355966
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485255 SCV000573475 uncertain significance not provided 2023-10-13 criteria provided, single submitter clinical testing Reported as p.A754V in an individual with episodic ataxia type 2 and abnormal EEG in published literature; however, segregation information was not provided, and it is unknown whether this individual was tested for variants in other associated genes (PMID: 33544220); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33544220)
Labcorp Genetics (formerly Invitae), Labcorp RCV001210428 SCV001381915 uncertain significance Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 754 of the CACNA1A protein (p.Ala754Val). This variant is present in population databases (rs200355966, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 423741). 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 expected to disrupt CACNA1A protein function with a positive predictive value of 95%. 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 RCV002446946 SCV002733392 uncertain significance Inborn genetic diseases 2017-09-25 criteria provided, single submitter clinical testing The p.A754V variant (also known as c.2261C>T), located in coding exon 18 of the CACNA1A gene, results from a C to T substitution at nucleotide position 2261. The alanine at codon 754 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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