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NM_001127222.2(CACNA1A):c.7318G>A (p.Val2440Ile) AND Developmental and epileptic encephalopathy, 42

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
May 21, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002471919.1

Allele description [Variation Report for NM_001127222.2(CACNA1A):c.7318G>A (p.Val2440Ile)]

NM_001127222.2(CACNA1A):c.7318G>A (p.Val2440Ile)

Gene:
CACNA1A:calcium voltage-gated channel subunit alpha1 A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.13
Genomic location:
Preferred name:
NM_001127222.2(CACNA1A):c.7318G>A (p.Val2440Ile)
HGVS:
  • NC_000019.10:g.13207516C>T
  • NG_011569.1:g.303945G>A
  • NM_000068.4:c.*530G>A
  • NM_001127221.2:c.*530G>A
  • NM_001127222.2:c.7318G>AMANE SELECT
  • NM_001174080.2:c.*530G>A
  • NM_023035.3:c.7336G>A
  • NP_001120694.1:p.Val2440Ile
  • NP_075461.2:p.Val2446Ile
  • LRG_7t1:c.*530G>A
  • LRG_7:g.303945G>A
  • NC_000019.9:g.13318330C>T
  • NM_001127221.1:c.*530G>A
  • NM_023035.2:c.7336G>A
Protein change:
V2440I
Molecular consequence:
  • NM_000068.4:c.*530G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001127221.2:c.*530G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001174080.2:c.*530G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001127222.2:c.7318G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_023035.3:c.7336G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Developmental and epileptic encephalopathy, 42 (DEE42)
Synonyms:
Epileptic encephalopathy, early infantile, 42
Identifiers:
MONDO: MONDO:0014917; MedGen: C4310716; OMIM: 617106

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002767559Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(May 21, 2020) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome.

Jiang X, Raju PK, D'Avanzo N, Lachance M, Pepin J, Dubeau F, Mitchell WG, Bello-Espinosa LE, Pierson TM, Minassian BA, Lacaille JC, Rossignol E.

Epilepsia. 2019 Sep;60(9):1881-1894. doi: 10.1111/epi.16316. Epub 2019 Aug 29.

PubMed [citation]
PMID:
31468518

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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767559.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. (PMID: 31468518) (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine (exon 48). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD in a region of low coverage. (N) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Val2446Glu); (1 heterozygote, 0 homozygotes)). (N) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 7, 2024