Submissions for variant NM_001127222.2(CACNA1A):c.2134G>A (p.Ala712Thr)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255263	SCV000321493	pathogenic	not provided	2022-01-21	criteria provided, single submitter	clinical testing	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: 27476654, 29186148, 23934111, 28488083, 26633542, 28455667, 31175295, 33425808, 29100083, 31468518, 32005694, 34102571, 34263451)
Ambry Genetics	RCV000623106	SCV000740986	likely pathogenic	Inborn genetic diseases	2015-08-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763034	SCV000893509	pathogenic	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42	2021-09-18	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000240888	SCV001164206	pathogenic	Developmental and epileptic encephalopathy, 42	2018-07-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000240888	SCV001423760	pathogenic	Developmental and epileptic encephalopathy, 42	2019-12-04	criteria provided, single submitter	clinical testing	The CACNA1A c.2137G>A (p.Ala713Thr) variant is a missense variant that has been reported in a heterozygous, de novo state in at least three unrelated individuals with epilepsy syndromes (Epi4K Consortium, Epilepsy Phenome/Genome Project 2013; Epi4K Consortium 2016; Balck et al. 2017). It was also identified in a fourth individual with seizures who had a similarly affected sibling. In this case, the variant was inherited from an unaffected parent who was mosaic for the variant with 6% mutational load in lymphocyte-derived DNA (Balck et al. 2017). In addition to early onset of multiple seizure types, individuals with this variant also showed abnormal movements in utero, ataxic movements and gait, mild dysmetria, dystonic posturing, and developmental delay/intellectual disability. The p.Ala713Thr variant is not found in the Genome Aggregation Database in a region of good sequencing coverage. Based on the collective evidence, the p.Ala713Thr variant is classified as pathogenic for early infantile epileptic encephalopathy.
Invitae	RCV001380078	SCV001578021	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2022-10-13	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 254268). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 23934111, 29186148). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 713 of the CACNA1A protein (p.Ala713Thr). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814128	SCV001755237	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Wendy Chung Laboratory, Columbia University Medical Center	RCV002227102	SCV002506538	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
3billion	RCV000240888	SCV002573050	likely pathogenic	Developmental and epileptic encephalopathy, 42	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.75). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000254268). A different missense change at the same codon (p.Ala712Ser) has been reported to be associated with CACNA1A -related disorder (ClinVar ID: VCV000997449). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000240888	SCV003761522	likely pathogenic	Developmental and epileptic encephalopathy, 42	2023-01-30	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 17 of the CACNA1A gene that results in the amino acid substitution of Threonine for Alanine at codon 712 (p.Ala712Thr) was detected. This variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a Likely Pathogenic.
OMIM	RCV000240888	SCV000299358	pathogenic	Developmental and epileptic encephalopathy, 42	2013-09-12	no assertion criteria provided	literature only
Cytoplasmic Inheritance Laboratory, Institute of Genetics and Cytology	RCV000240888	SCV002522444	likely pathogenic	Developmental and epileptic encephalopathy, 42	2022-05-31	no assertion criteria provided	clinical testing	We consider the variant NM_001127221.2:c.2137G>A as disease-causing; it results in an amino acid substitution p.Ala713Thr.
GenomeConnect - Brain Gene Registry	RCV002274954	SCV002564396	not provided	Episodic ataxia type 2; Familial hemiplegic migraine; Developmental and epileptic encephalopathy, 42		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 08-12-2015 by lab or GTR ID 61756. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IIDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.