Submissions for variant NM_001127222.2(CACNA1A):c.653C>T (p.Ser218Leu)

dbSNP: rs121908225

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502832	SCV000593820	pathogenic	Episodic ataxia type 2	2016-05-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390632	SCV001592428	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 218 of the CACNA1A protein (p.Ser218Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hemiplegic migraine (PMID: 11409427, 19520699). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8504). 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. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 15743764, 18581134). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002272012	SCV002558407	pathogenic	not provided	2022-07-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging gain of function effect (Kaja et al., 2015; Tottene et al., 2005); 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: 18313928, 19520699, 19104150, 24498617, 23985897, 26208839, 29761117, 20186955, 19438926, 19242091, 22144569, 20071244, 25741235, 23115190, 24849341, 25716839, 21824570, 18581134, 11409427, 26814174, 22784462, 23673147, 28007337, 33023723, 29915382, 30649209, 15743764, 27476654, 33084218, 27535533)
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV003150928	SCV003840190	likely pathogenic	Developmental and epileptic encephalopathy, 42	2021-05-28	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000502832	SCV003923318	pathogenic	Episodic ataxia type 2		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.653C>T in Exon 5 of the CACNA1A gene that results in the amino acid substitution p.Ser218Leu was identified. The observed variant has a minor allele frequency of 0.00% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic. (Variation ID: 8504) The variant has been previously reported by Kors EE, et al., 2001. Functional studies demonstrate a damaging gain of function effect (Damaj L et al., 2015) Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003150928	SCV004241106	pathogenic	Developmental and epileptic encephalopathy, 42	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: CACNA1A c.653C>T (p.Ser218Leu) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248928 control chromosomes (gnomAD). c.653C>T has been reported in the literature in multiple individuals affected with Familial hemiplegic migraine (examples: Kors_2001, Stam_2009). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11409427, 19520699). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV002272012	SCV005197354	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000009027	SCV000029243	pathogenic	Migraine, familial hemiplegic, 1	2013-09-12	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000009027	SCV000090872	not provided	Migraine, familial hemiplegic, 1		no assertion provided	not provided
GeneReviews	RCV001533157	SCV001748976	not provided	Familial hemiplegic migraine		no assertion provided	literature only