Submissions for variant NM_001127222.2(CACNA1A):c.2133C>G (p.Ile711Met)

dbSNP: rs764839814

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519829	SCV000618721	likely pathogenic	not provided	2017-11-30	criteria provided, single submitter	clinical testing	The I712M variant in the CACNA1A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I712M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I712M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A different missense variant in the same residue (I712V) has been reported as heterozygous de novo in a female with seizures, ataxia, headaches, developmental regression, intellectual disability, and mild cerebellar atrophy (Guerin et al., 2008). In addition, missense variants in nearby residues (A713T, V714A, D715E) have been reported in the Human Gene Mutation Database in association with CACNA1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret I712M as a likely pathogenic variant.
Invitae	RCV001853632	SCV002208573	uncertain significance	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2020-12-30	criteria provided, single submitter	clinical testing	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. 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 not been reported in the literature in individuals with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 450171). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 712 of the CACNA1A protein (p.Ile712Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine.
Wendy Chung Laboratory, Columbia University Medical Center	RCV002227178	SCV002506539	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
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV003492089	SCV004232712	likely pathogenic	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42	2023-12-14	criteria provided, single submitter	research