NM_172107.4(KCNQ2):c.2T>A (p.Met1Lys) AND Early infantile epileptic encephalopathy with suppression bursts

Clinical significance:Pathogenic (Last evaluated: Dec 2, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000809476.1

Allele description [Variation Report for NM_172107.4(KCNQ2):c.2T>A (p.Met1Lys)]

NM_172107.4(KCNQ2):c.2T>A (p.Met1Lys)

Gene:
KCNQ2:potassium voltage-gated channel subfamily Q member 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
20q13.33
Genomic location:
Preferred name:
NM_172107.4(KCNQ2):c.2T>A (p.Met1Lys)
HGVS:
  • NC_000020.11:g.63472462A>T
  • NG_009004.2:g.5179T>A
  • NM_004518.6:c.2T>A
  • NM_172106.3:c.2T>A
  • NM_172107.4:c.2T>AMANE SELECT
  • NM_172108.5:c.2T>A
  • NM_172109.3:c.2T>A
  • NP_004509.2:p.Met1Lys
  • NP_742104.1:p.Met1Lys
  • NP_742105.1:p.Met1Lys
  • NP_742106.1:p.Met1Lys
  • NP_742107.1:p.Met1Lys
  • NC_000020.10:g.62103815A>T
  • NM_172107.2:c.2T>A
Protein change:
M1K
Links:
dbSNP: rs118192186
NCBI 1000 Genomes Browser:
rs118192186
Molecular consequence:
  • NM_004518.6:c.2T>A - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_172106.3:c.2T>A - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_172107.4:c.2T>A - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_172108.5:c.2T>A - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_172109.3:c.2T>A - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_004518.6:c.2T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172106.3:c.2T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172107.4:c.2T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172108.5:c.2T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172109.3:c.2T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Early infantile epileptic encephalopathy with suppression bursts (EIEE)
Synonyms:
Early infantile epileptic encephalopathy; Ohtahara syndrome; Developmental and epileptic encephalopathy
Identifiers:
MONDO: MONDO:0100062; MedGen: C0393706; Orphanet: 1934; OMIM: PS308350

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000949628Invitaecriteria provided, single submitter
Pathogenic
(Dec 2, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits.

Miceli F, Soldovieri MV, Ambrosino P, De Maria M, Migliore M, Migliore R, Taglialatela M.

J Neurosci. 2015 Mar 4;35(9):3782-93. doi: 10.1523/JNEUROSCI.4423-14.2015.

PubMed [citation]
PMID:
25740509
PMCID:
PMC6605567

De novo mutations in epileptic encephalopathies.

Epi4K Consortium.; Epilepsy Phenome/Genome Project., Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Glauser T, Goldstein DB, Han Y, Heinzen EL, Hitomi Y, Howell KB, Johnson MR, Kuzniecky R, Lowenstein DH, Lu YF, Madou MR, Marson AG, Mefford HC, et al.

Nature. 2013 Sep 12;501(7466):217-21. doi: 10.1038/nature12439. Epub 2013 Aug 11.

PubMed [citation]
PMID:
23934111
PMCID:
PMC3773011
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000949628.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change affects the initiator methionine of the KCNQ2 mRNA. The next in-frame methionine is located at codon 174. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. Disruption of the initiator codon has been observed to segregate with familial neonatal seizures in several families (PMID: 14985406, 25982755, Invitae). ClinVar contains an entry for this variant (Variation ID: 497690). Experimental studies have not been reported for this initiator codon variant and its effect on protein expression is unknown. However, a missense variant located upstream of the next in-frame methionine (p.Arg144Gln) has been determined to be pathogenic (PMID: 23934111, 25740509). This suggests that even if translation is rescued by an in-frame methionine, deletion of the N-terminal region of the KCNQ2 protein is likely to be deleterious. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: May 7, 2021

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