Submissions for variant NM_001127222.2(CACNA1A):c.29C>T (p.Ala10Val)

gnomAD frequency: 0.00002  dbSNP: rs952757731

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481875	SCV000572057	uncertain significance	not provided	2017-06-12	criteria provided, single submitter	clinical testing	The A10V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A10V variant is not observed in large population cohorts; however, limited data are available (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A10V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and this substitution occurs at a position that is not conserved. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697164	SCV000825761	uncertain significance	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-12-02	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 10 of the CACNA1A protein (p.Ala10Val). This variant is not present in population databases (gnomAD no frequency). 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: 422558). 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 CACNA1A protein function with a negative 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.
New York Genome Center	RCV001839005	SCV002099398	uncertain significance	Developmental and epileptic encephalopathy, 42	2021-03-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003258820	SCV003975008	uncertain significance	Inborn genetic diseases	2023-05-01	criteria provided, single submitter	clinical testing	The c.29C>T (p.A10V) alteration is located in exon 1 (coding exon 1) of the CACNA1A gene. This alteration results from a C to T substitution at nucleotide position 29, causing the alanine (A) at amino acid position 10 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.