NM_172107.4(KCNQ2):c.1030T>C (p.Trp344Arg) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 18, 2022
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:: RCV002523838.3

Allele description [Variation Report for NM_172107.4(KCNQ2):c.1030T>C (p.Trp344Arg)]

NM_172107.4(KCNQ2):c.1030T>C (p.Trp344Arg)

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.1030T>C (p.Trp344Arg)

HGVS:

NC_000020.11:g.63433897A>G
NG_009004.2:g.43744T>C
NM_004518.6:c.1030T>C
NM_172106.3:c.1030T>C
NM_172107.4:c.1030T>CMANE SELECT
NM_172108.5:c.1030T>C
NM_172109.3:c.1030T>C
NP_004509.2:p.Trp344Arg
NP_742104.1:p.Trp344Arg
NP_742105.1:p.Trp344Arg
NP_742106.1:p.Trp344Arg
NP_742107.1:p.Trp344Arg
NC_000020.10:g.62065250A>G
NM_172107.2:c.1030T>C

Protein change:

W344R

Links:

dbSNP: rs1057516105

NCBI 1000 Genomes Browser:

rs1057516105

Molecular consequence:

NM_004518.6:c.1030T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172106.3:c.1030T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172107.4:c.1030T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172108.5:c.1030T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_172109.3:c.1030T>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003443384	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 18, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26073431, 34020651, 24375629, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003443384

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 18, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Epilepsy-causing mutations in Kv7.2 C-terminus affect binding and functional modulation by calmodulin.

Ambrosino P, Alaimo A, Bartollino S, Manocchio L, De Maria M, Mosca I, Gomis-Perez C, Alberdi A, Scambia G, Lesca G, Villarroel A, Taglialatela M, Soldovieri MV.

Biochim Biophys Acta. 2015 Sep;1852(9):1856-66. doi: 10.1016/j.bbadis.2015.06.012. Epub 2015 Jun 12.

PubMed [citation]

PMID:: 26073431

An epilepsy-causing mutation leads to co-translational misfolding of the Kv7.2 channel.

Urrutia J, Aguado A, Gomis-Perez C, Muguruza-Montero A, Ballesteros OR, Zhang J, Nuñez E, Malo C, Chung HJ, Leonardo A, Bergara A, Villarroel A.

BMC Biol. 2021 May 21;19(1):109. doi: 10.1186/s12915-021-01040-1.

PubMed [citation]

PMID:: 34020651
PMCID:: PMC8138981

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443384.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 24375629, 26073431, 34020651). 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: 369777). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 24375629). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 344 of the KCNQ2 protein (p.Trp344Arg).

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

Last Updated: Sep 29, 2024

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