Submissions for variant NM_001127222.2(CACNA1A):c.4997G>C (p.Arg1666Pro)

dbSNP: rs1568447650

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV003985429	SCV000930558	likely pathogenic	CACNA1A-related disorder	2019-02-10	criteria provided, single submitter	clinical testing
Invitae	RCV001869248	SCV002138475	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2021-04-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1667 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11439943). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been observed in individual(s) with clinical features of CACNA1A-related conditions (PMID: 32170034). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 638582). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 1667 of the CACNA1A protein (p.Arg1667Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline.
Wendy Chung Laboratory, Columbia University Medical Center	RCV002227217	SCV002506554	likely pathogenic	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 52	2022-03-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002535839	SCV003552390	likely pathogenic	Inborn genetic diseases	2021-01-25	criteria provided, single submitter	clinical testing	The c.5000G>C (p.R1667P) alteration is located in exon 32 (coding exon 32) of the CACNA1A gene. This alteration results from a G to C substitution at nucleotide position 5000, causing the arginine (R) at amino acid position 1667 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD), the CACNA1A c.5000G>C alteration was not observed, with coverage at this position. This alteration was detected as de novo in a child with severe CACNA1A-related disorder who experienced cerebellar ataxia, dysarthria, generalized dystonia, and refractory, fatal brain edema (Gauquelin, 2020). Another alteration at the same codon, p.R1667W (c.4999C>T), has been detected in a mother and daughter with symptoms of episodic ataxia and familial hemiplegic migraine (Marti, 2008) and in over ten individuals individuals with familial hemiplegic migraines (Indelicato, 2019; Ducros, 2001). This amino acid position is highly conserved in available vertebrate species. The p.R1667P alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.