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NM_172107.4(KCNQ2):c.430C>T (p.Arg144Trp) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 28, 2023
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:
RCV002525240.5

Allele description [Variation Report for NM_172107.4(KCNQ2):c.430C>T (p.Arg144Trp)]

NM_172107.4(KCNQ2):c.430C>T (p.Arg144Trp)

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.430C>T (p.Arg144Trp)
Other names:
KCNQ2
HGVS:
  • NC_000020.11:g.63445322G>A
  • NG_009004.2:g.32319C>T
  • NM_004518.6:c.430C>T
  • NM_172106.3:c.430C>T
  • NM_172107.4:c.430C>TMANE SELECT
  • NM_172108.5:c.430C>T
  • NM_172109.3:c.430C>T
  • NP_004509.2:p.Arg144Trp
  • NP_742104.1:p.Arg144Trp
  • NP_742105.1:p.Arg144Trp
  • NP_742106.1:p.Arg144Trp
  • NP_742107.1:p.Arg144Trp
  • NC_000020.10:g.62076675G>A
  • NM_172107.2:c.430C>T
  • NM_172107.3:c.430C>T
Protein change:
R144W
Links:
Molecular consequence:
  • NM_004518.6:c.430C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172106.3:c.430C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172107.4:c.430C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172108.5:c.430C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172109.3:c.430C>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
  • Moderate decrease in peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0086]
  • Severe hyperpolarizing shift of voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0031]
  • Severe slowing of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0015]

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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003443825Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Mar 28, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy.

Mary L, Nourisson E, Feger C, Laugel V, Chaigne D, Keren B, Afenjar A, Billette T, Trost D, Cieuta-Walti C, Gerard B, Piton A, Schaefer E.

Am J Med Genet A. 2021 Jun;185(6):1803-1815. doi: 10.1002/ajmg.a.62181. Epub 2021 Mar 23.

PubMed [citation]
PMID:
33754465

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 (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443825.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 33754465). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg144 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23934111, 25740509). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ2 protein function. ClinVar contains an entry for this variant (Variation ID: 452487). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 144 of the KCNQ2 protein (p.Arg144Trp).

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

Last Updated: Oct 26, 2024