rs778291283

Variant names:

• chr1-181720261-A-C
• rs778291283
• NM_001205293.3:c.1807A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-181720261-A-C
• chr1-181720261-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001205293.3(CACNA1E):​c.1807A>C​(p.Ile603Leu) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.20

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• PP5: Variant 1-181720261-A-C is Pathogenic according to our data. Variant chr1-181720261-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 390468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-181720261-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.1807A>C	p.Ile603Leu	missense_variant	Exon 14 of 48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.1807A>C	p.Ile603Leu	missense_variant	Exon 14 of 48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.1807A>C	p.Ile603Leu	missense_variant	Exon 14 of 47	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.1807A>C	p.Ile603Leu	missense_variant	Exon 14 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.1807A>C	p.Ile603Leu	missense_variant	Exon 14 of 46	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 69 Pathogenic:2

Nov 18, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 69 (MIM#618285; PMID: 30343943). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions but in a highly conserved residue. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER) and in the domain II S4-S5 linker region (PMID: 30343943). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in a child with focal motor seizures, hypotonia and severe developmental delay (PMID: 30343943). (SP) 0905 - No published segregation evidence has been identified for this variant. Causative CACNA1E variants have been reported as de novo in the published literature. (I) 1002 - Moderate functional evidence supporting abnormal protein function. Patch clamp studies show increased current density and hyperpolarisation shift in tsA201 cells with this variant compared with wild-type (PMID: 30343943). However, patch clamp assays have been shown to be unreliable and therefore, results from these studies are used with caution during variant classification. (I) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) by trio analysis. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Nov 01, 2018

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 31, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The confirmed de novo I603L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server, 2016; McVean et al., 2012). The I603L variant is a conservative amino acid substitution that occurs at a conserved position predicted to be in the intracellular loop between the S4 and S5 transmembrane segments of the second homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	.;.;.;D;T;.;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;.;D;.;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	L;L;.;L;.;L;L;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.9	N;.;N;N;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Benign	0.12	T;.;T;T;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		0.94	P;P;.;.;.;P;.;P
Vest4		0.65
MutPred		0.67		Loss of ubiquitination at K601 (P = 0.1231);Loss of ubiquitination at K601 (P = 0.1231);Loss of ubiquitination at K601 (P = 0.1231);Loss of ubiquitination at K601 (P = 0.1231);Loss of ubiquitination at K601 (P = 0.1231);Loss of ubiquitination at K601 (P = 0.1231);Loss of ubiquitination at K601 (P = 0.1231);Loss of ubiquitination at K601 (P = 0.1231);
MVP		0.87
MPC		1.2
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.37
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778291283; hg19: chr1-181689397;