NM_172107.4(KCNQ2):c.704C>G (p.Ala235Gly) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 14, 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:: RCV002710198.3

Allele description [Variation Report for NM_172107.4(KCNQ2):c.704C>G (p.Ala235Gly)]

NM_172107.4(KCNQ2):c.704C>G (p.Ala235Gly)

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.704C>G (p.Ala235Gly)

HGVS:

NC_000020.11:g.63442518G>C
NG_009004.2:g.35123C>G
NM_001382235.1:c.704C>G
NM_004518.6:c.704C>G
NM_172106.3:c.704C>G
NM_172107.4:c.704C>GMANE SELECT
NM_172108.5:c.704C>G
NM_172109.3:c.704C>G
NP_001369164.1:p.Ala235Gly
NP_004509.2:p.Ala235Gly
NP_742104.1:p.Ala235Gly
NP_742105.1:p.Ala235Gly
NP_742106.1:p.Ala235Gly
NP_742107.1:p.Ala235Gly
NC_000020.10:g.62073871G>C

Protein change:

A235G

Molecular consequence:

NM_001382235.1:c.704C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004518.6:c.704C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172106.3:c.704C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172107.4:c.704C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172108.5:c.704C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172109.3:c.704C>G - 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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iron-regulated membrane protein [Klebsiella pneumoniae]
iron-regulated membrane protein [Klebsiella pneumoniae]
gi|1429170869|emb|SSI18074.1||gnl|W DL|SSI18074

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002996017	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 14, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31418850, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002996017

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 14, 2022)

germline

clinical testing

PubMed (2)
[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

Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy.

Goto A, Ishii A, Shibata M, Ihara Y, Cooper EC, Hirose S.

Epilepsia. 2019 Sep;60(9):1870-1880. doi: 10.1111/epi.16314. Epub 2019 Aug 16.

PubMed [citation]

PMID:: 31418850

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002996017.2

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

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. This variant disrupts the p.Ala235 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ2-related conditions (PMID: 31418850; Invitae), which suggests that this may be a clinically significant amino acid residue. 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. This missense change has been observed in individual(s) with clinical features of KCNQ2-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 235 of the KCNQ2 protein (p.Ala235Gly).

#	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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