Submissions for variant NM_001127222.2(CACNA1A):c.5393C>T (p.Ser1798Leu)

dbSNP: rs1064794261

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485872	SCV000568529	pathogenic	not provided	2022-07-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32899500, 32458086, 24091540, 32116539, 35219921, Kubota2021[Case Report])
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000853325	SCV000996179	pathogenic	Developmental and epileptic encephalopathy, 42	2018-07-30	criteria provided, single submitter	clinical testing	This variant has been previously reported as a pathogenic variant by a clinical laboratory in ClinVar (Variation ID: 420055) and has been reported de novo change in a patient with ataxia, dysmetria, oculomotor apraxia, intention tremor, developmental delay, intellectual disability, lack of speech, hypotonia, and epileptic seizures (PMID: 24091540). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.5393C>T (p.Ser1798Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples showed the mother is negative and the father is negative for this variant, indicating an apparently de novo event. Based on the available evidence, the c.5393C>T (p.Ser1798Leu) variant is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000485872	SCV001446865	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000853325	SCV001529548	pathogenic	Developmental and epileptic encephalopathy, 42	2018-02-06	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as a de novo disease causing variant in an 8-year-old individual with cerebellar atrophy, developmental delay and hypotonia [PMID 24091540]
Invitae	RCV001851179	SCV002238572	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2021-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine with leucine at codon 1799 of the CACNA1A protein (p.Ser1799Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with CACNA1A-related conditions (PMID: 24091540). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 420055). 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. For these reasons, this variant has been classified as Pathogenic.
Wendy Chung Laboratory, Columbia University Medical Center	RCV002227166	SCV002506545	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