Submissions for variant NM_001127222.2(CACNA1A):c.5422G>A (p.Val1808Ile)

gnomAD frequency: 0.00001  dbSNP: rs1296629000

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001916764	SCV002196739	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1809 of the CACNA1A protein (p.Val1809Ile). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with CACNA1A-related conditions (PMID: 35722745; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.5422G>A (p.Val1808Ile) in transcript NM_001127222. ClinVar contains an entry for this variant (Variation ID: 1421109). 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 disrupts the p.Val1809 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been observed in individuals with CACNA1A-related conditions (PMID: 28927557), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Wendy Chung Laboratory, Columbia University Medical Center	RCV002227288	SCV002506523	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