NM_001205293.3(CACNA1E):c.1054G>A (p.Gly352Arg) AND Developmental and epileptic encephalopathy, 69

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Oct 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000754086.15

Allele description [Variation Report for NM_001205293.3(CACNA1E):c.1054G>A (p.Gly352Arg)]

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

Gene:

CACNA1E:calcium voltage-gated channel subunit alpha1 E [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q25.3

Genomic location:

Preferred name:

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

HGVS:

NC_000001.11:g.181651440G>A
NG_050616.1:g.173130G>A
NM_000721.4:c.1054G>A
NM_001205293.3:c.1054G>AMANE SELECT
NM_001205294.2:c.1054G>A
NP_000712.2:p.Gly352Arg
NP_001192222.1:p.Gly352Arg
NP_001192223.1:p.Gly352Arg
NC_000001.10:g.181620576G>A
NM_000721.3:c.1054G>A
NM_001205293.1:c.1054G>A

Protein change:

G352R; GLY352ARG

Links:

OMIM: 601013.0005; dbSNP: rs886039323

NCBI 1000 Genomes Browser:

rs886039323

Molecular consequence:

NM_000721.4:c.1054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001205293.3:c.1054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001205294.2:c.1054G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 69
Synonyms:: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 69
Identifiers:: MONDO: MONDO:0032657; MedGen: C4748988; OMIM: 618285

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BioProject Links for Nucleotide (Select 1578795725) (1)
BioProject
Protein Links for Nucleotide (Select 2102931011) (23)
Protein
cytochrome oxidase subunit 1, partial (mitochondrion) [Telenomus sp. BIOUG25428-...
cytochrome oxidase subunit 1, partial (mitochondrion) [Telenomus sp. BIOUG25428-G11]
gi|1578795726|gb|QBF40353.1|

Protein
Protein Links for Nucleotide (Select 2102930996) (1000)
Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000882421	OMIM	no assertion criteria provided	Pathogenic (Nov 18, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001150035	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Apr 3, 2019)	de novo, germline	clinical testing	Citation Link,
SCV001429013	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003842098	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30343943, 25741868
SCV004046876	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2023)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30343943, 25741868
SCV004179579	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005091527	Solve-RD Consortium	no assertion criteria provided	Likely pathogenic (Jun 1, 2022)	inherited	provider interpretation

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	provider interpretation
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, et al.

Am J Hum Genet. 2018 Nov 1;103(5):666-678. doi: 10.1016/j.ajhg.2018.09.006. Epub 2018 Oct 18. Erratum in: Am J Hum Genet. 2019 Mar 7;104(3):562. doi: 10.1016/j.ajhg.2019.02.015.

PubMed [citation]

PMID:: 30343943
PMCID:: PMC6216110

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000882421.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 9 unrelated patients (patients 3-11) with developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified a de novo heterozygous c.1054G-A transition (c.1054G-A, NM_000721.3) in the CACNA1E gene, resulting in a gly352-to-arg (G352R) substitution in the cytoplasmic end of the S6 transmembrane segment of domain I. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. Functional expression studies of the variant were not performed. The patients had onset of various types of seizures between 2 months and 3 years of age.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001150035.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided
2	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429013.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

_x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM2_SUP, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003842098.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, SCV004046876.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (2)

Description

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"

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004179579.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Solve-RD Consortium, SCV005091527.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

Description

Variant confirmed as disease-causing by referring clinical team

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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