rs886039323

Positions:

• chr1-181651440-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001205293.3(CACNA1E):​c.1054G>A​(p.Gly352Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1E NM_001205293.3 missense, splice_region
• Scores: Splicing: ADA: 0.9509
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.43

Genes affected

CACNA1E (HGNC:1392): (calcium voltage-gated channel subunit alpha1 E) Voltage-dependent calcium channels are multisubunit complexes consisting of alpha-1, alpha-2, beta, and delta subunits in a 1:1:1:1 ratio. These channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. This gene encodes the alpha-1E subunit of the R-type calcium channels, which belong to the 'high-voltage activated' group that maybe involved in the modulation of firing patterns of neurons important for information processing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a repeat I (size 278) in uniprot entity CAC1E_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001205293.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1E. . Gene score misZ 5.8125 (greater than the threshold 3.09). Trascript score misZ 6.7013 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 69.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 1-181651440-G-A is Pathogenic according to our data. Variant chr1-181651440-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-181651440-G-A is described in Lovd as [Pathogenic]. Variant chr1-181651440-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.1054G>A	p.Gly352Arg	missense_variant, splice_region_variant	7/48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.1054G>A	p.Gly352Arg	missense_variant, splice_region_variant	7/48	1	NM_001205293.3	ENSP00000356545	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 69 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Oct 23, 2023	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" -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 02, 2022	_x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM2_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Apr 03, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 18, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 31, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	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. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2018

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Nov 01, 2018

- -

CACNA1E-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;.;D;D;.;D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;M;M;.;M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-6.1	.;D;.;D;D;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0060	.;D;.;D;D;.;.;.;.
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;.;.;D;.;D
Vest4		0.90, 0.96, 0.91, 0.89, 0.82, 0.91, 0.90, 0.94
MutPred		0.63		.;Gain of MoRF binding (P = 0.0479);Gain of MoRF binding (P = 0.0479);Gain of MoRF binding (P = 0.0479);Gain of MoRF binding (P = 0.0479);Gain of MoRF binding (P = 0.0479);Gain of MoRF binding (P = 0.0479);Gain of MoRF binding (P = 0.0479);Gain of MoRF binding (P = 0.0479);
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886039323; hg19: chr1-181620576; COSMIC: COSV100705521;