Submissions for variant NM_001127222.2(CACNA1A):c.1594G>A (p.Glu532Lys)

gnomAD frequency: 0.00001  dbSNP: rs1064794263

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487043	SCV000568532	likely pathogenic	not provided	2022-07-27	criteria provided, single submitter	clinical testing	Also reported in an individual and sibling with a history of benign paroxysmal torticollis of infancy (BPT1) and observed in their asymptomatic mother (Vila-Pueyo et al., 2014); Published functional studies show that E533K impairs ion channel function (Vila-Pueyo et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24445160, 27066515, 31175295, 33349592, 16583725)
Revvity Omics, Revvity	RCV000487043	SCV002025036	likely pathogenic	not provided	2020-12-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470870	SCV002767856	pathogenic	Episodic ataxia type 2	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with episodic ataxia type 2 (EA2; MIM# 108500) and hemiplegic migraine, respectively (PMID: 28566750). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - EA2 associated with this gene has incomplete penetrance (PMID: 10408533). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER) within the transmembrane region (PMID: 27066515) of the ion transport protein domain (Decipher, PDB, NCBI). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals with EA2 (ClinVar; PMIDs: 16583725, 27066515). In addition, this variant has been reported in two siblings with benign paroxysmal torticollis of infancy (BPTI), inherited from asymptomatic mother (PMID: 24445160). (SP) 0903 - This variant has limited evidence for segregation in one family with EA2 (PMID: 16583725). (SP) 1002 - Limited functional evidence supporting abnormal protein function. Patch clamp studies using HEK293 cells showed a loss of function effect of the channel activity due to impaired gating by voltage and lowered current density (PMID: 24445160). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (N) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae	RCV002526562	SCV003297479	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2022-09-07	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 420057). This missense change has been observed in individuals with clinical features of CACNA1A-related conditions and/or episodic ataxia type 2 (PMID: 16583725, 24445160, 27066515; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 533 of the CACNA1A protein (p.Glu533Lys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 24445160).
Genetic Services Laboratory, University of Chicago	RCV000487043	SCV003839301	likely pathogenic	not provided	2022-06-13	no assertion criteria provided	clinical testing	DNA sequence analysis of the CACNA1A gene demonstrated a sequence change, c.1597G>A, in exon 12 that results in an amino acid change, p.Glu533Lys. The p.Glu533Lys change affects a highly conserved amino acid residue located in a domain of the CACNA1A protein that is known to be functional. This sequence change has not been described in population databases such as ExAC and gnomAD. This sequence change has been described in individuals with CACNA1A-related disorders (PMID: 16583725, 27066515, 24445160). Functional studies have shown that this variant causes impaired ion channel function (PMID: 24445160). The p.Glu533Lys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Based on these evidence this sequence change is classified as likely pathogenic.