Submissions for variant NM_001205293.3(CACNA1E):c.1054G>A (p.Gly352Arg)

dbSNP: rs886039323

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255319	SCV000321496	pathogenic	not provided	2021-12-10	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); 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: 30343943, 32695065)
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000754086	SCV001150035	pathogenic	Developmental and epileptic encephalopathy, 69	2019-04-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000754086	SCV001429013	pathogenic	Developmental and epileptic encephalopathy, 69	2022-02-02	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM2_SUP, PP3
Ambry Genetics	RCV001266668	SCV001444845	likely pathogenic	Inborn genetic diseases	2018-05-15	criteria provided, single submitter	clinical testing
Invitae	RCV000255319	SCV003256100	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 352 of the CACNA1E protein (p.Gly352Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 30343943). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265066). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000255319	SCV003802795	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing	The CACNA1E c.1054G>A (p.Gly352Arg) missense variant results in substitution of glycine at amino acid position 352 with arginine. This variant has been reported in a heterozygous state in at least 13 individuals with developmental and epileptic encephalopathy (PMID: 30343943; PMID: 32695065; PMID: 33776624; PMID: 35937981). Of these, all are WES or WGS studies and five have confirmed de novo inheritance. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.1054G>A (p.Gly352Arg) variant is classified as pathogenic for CACNA1E-related developmental and epileptic encephalopathy.
3billion	RCV000754086	SCV003842098	pathogenic	Developmental and epileptic encephalopathy, 69	2023-02-23	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: 0.91; 3Cnet: 0.69). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265066). The variant has been previously reported as de novo in a similarly affected individual (PMID: 30343943, 30343943). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 30343943). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000754086	SCV004046876	pathogenic	Developmental and epileptic encephalopathy, 69	2023-10-23	criteria provided, single submitter	clinical testing	This heterozygous mis-sense variant is identified in a 9 month female with perinatal asphyxia, myoclonic seizures, DD, hypotonia, MRI Brain with T2 hyper-intensities in globus pallidus. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [REVEL=0.91] predicts deleterious nature of this variant. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 265066] with “Pathogenic/Likely Pathogenic” interpretation by multiple submitter [PP5]. Parental segregation confirmed the de-novo status of this variant [PM6]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic"
PreventionGenetics, part of Exact Sciences	RCV003417866	SCV004106146	pathogenic	CACNA1E-related condition	2023-05-29	criteria provided, single submitter	clinical testing	The CACNA1E c.1054G>A variant is predicted to result in the amino acid substitution p.Gly352Arg. This variant has been reported as a recurrent de novo finding in individuals with autosomal dominant epileptic encephalopathy (Helbig et al. 2018. PubMed ID: 30343943, Table 1; OMIM #618285). Clinical features in affected individuals included seizures, hypotonia, hypertonia, dystonia, MRI abnormalities, profound developmental delay, macrocephaly, and contractures. This variant was also described as likely pathogenic in an individual who was tested as part of an epilepsy panel, but the phenotype of this patient was not given (Won et al. 2020. PubMed ID: 32695065). This variant is absent in the gnomAD population database, indicating that it is very rare. In ClinVar, this variant is interpreted as pathogenic and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/265066/). In summary, this variant is interpreted as pathogenic.
Genome-Nilou Lab	RCV000754086	SCV004179579	likely pathogenic	Developmental and epileptic encephalopathy, 69	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000754086	SCV000882421	pathogenic	Developmental and epileptic encephalopathy, 69	2020-11-18	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV001849352	SCV002106530	likely pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2018-11-01	no assertion criteria provided	literature only