ClinVar Miner

Submissions for variant NM_023035.3(CACNA1A):c.4186G>A (p.Val1396Met) (rs794727411)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000176622 SCV000228310 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000176622 SCV000322140 pathogenic not provided 2018-12-14 criteria provided, single submitter clinical testing The V1393M variant in the CACNA1A gene has been reported previously as a de novo variant in an individual with childhood onset ataxia, seizures, intellectual disability, and cerebellar atrophy (Travaglini et al., 2017). The V1393M variant is not observed in large population cohorts (Lek et al., 2016). The V1393M 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. The V1393M variant is within transmembrane segment S5 in the third homologous domain of the protein. We interpret V1393M as a pathogenic variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000604986 SCV000731256 likely pathogenic Epileptic encephalopathy, early infantile, 42 2017-12-14 criteria provided, single submitter research
Ambry Genetics RCV000623848 SCV000741273 uncertain significance Inborn genetic diseases 2016-03-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000604986 SCV000784524 likely pathogenic Epileptic encephalopathy, early infantile, 42 2018-03-05 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000662176 SCV000784525 likely pathogenic Migraine 2018-03-05 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000662177 SCV000784526 likely pathogenic Episodic ataxia type 2 2018-03-05 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000662178 SCV000784527 likely pathogenic Spinocerebellar ataxia type 6 2018-03-05 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000662179 SCV000784528 likely pathogenic Familial hemiplegic migraine type 1 2018-03-05 criteria provided, single submitter clinical testing
Invitae RCV001061471 SCV001226215 likely pathogenic Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2019-09-12 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1393 of the CACNA1A protein (p.Val1393Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with ataxia, tremor, developmental delay, and epilepsy (PMID: 28007337, 30283815) as well as individuals with epileptic encephalopathy (PMID: 29056246, 29100083). In at least one individual the variant was observed to be de novo. It is also known as NM_023035.2:c.4186G>A (p.V1396M) in the literature. ClinVar contains an entry for this variant (Variation ID: 195935). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198190 SCV001369060 likely pathogenic Epilepsy 2019-05-07 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. This variant was detected in heterozygous state.
Baylor Genetics RCV000415108 SCV000328711 likely pathogenic Episodic ataxia type 2; Familial hemiplegic migraine type 1 2014-10-16 no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in CACNA1A (NM_001174080.1, c.4177G>A) and SLC26A1 (NM_022042.2, c.1487T>G) in one individual with reported features of intractable epilepsy, global developmental delay, tremor, ataxia, hyperlipidemia, growth hormone deficiency, and stable right optic nerve glioma. Missense and truncating variants in CACNA1A have been reported in patients with epilepsy (PMID:18940563;PMID:21703448)

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