Submissions for variant NM_001127222.2(CACNA1A):c.3143G>A (p.Arg1048Gln)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004432167	SCV004916236	uncertain significance	Inborn genetic diseases	2023-12-14	criteria provided, single submitter	clinical testing	The c.3146G>A (p.R1049Q) alteration is located in exon 20 (coding exon 20) of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 3146, causing the arginine (R) at amino acid position 1049 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV004577047	SCV005061200	uncertain significance	Developmental and epileptic encephalopathy, 42		criteria provided, single submitter	clinical testing	The missense variant c.3143G>A(p.Arg1048Gln) in the CACNA1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is absent in gnomAD Exomes. The amino acid Arginine at position 1048 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg1048Gln in CACNA1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV005023528	SCV005655090	uncertain significance	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42	2024-03-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005220891	SCV005865956	uncertain significance	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2024-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1049 of the CACNA1A protein (p.Arg1049Gln). 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: 3136302). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.