NM_172107.4(KCNQ2):c.910TTC[1] (p.Phe305del) AND KCNQ2-related disorder

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 26, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001836639.8

Allele description [Variation Report for NM_172107.4(KCNQ2):c.910TTC[1] (p.Phe305del)]

NM_172107.4(KCNQ2):c.910TTC[1] (p.Phe305del)

Gene:

KCNQ2:potassium voltage-gated channel subfamily Q member 2 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

20q13.33

Genomic location:

Preferred name:

NM_172107.4(KCNQ2):c.910TTC[1] (p.Phe305del)

Other names:

F304delF

HGVS:

NC_000020.11:g.63439611AAG[1]
NG_009004.2:g.38026TTC[1]
NM_001382235.1:c.910TTC[1]
NM_004518.6:c.910TTC[1]
NM_172106.3:c.910TTC[1]
NM_172107.4:c.910TTC[1]MANE SELECT
NM_172107.4:c.913_915delTTC
NM_172108.5:c.910TTC[1]
NM_172109.3:c.910TTC[1]
NP_001369164.1:p.Phe305del
NP_004509.2:p.Phe305del
NP_742104.1:p.Phe305del
NP_742105.1:p.Phe305del
NP_742106.1:p.Phe305del
NP_742107.1:p.Phe305del
NC_000020.10:g.62070963_62070965del
NC_000020.10:g.62070963_62070965delGAA
NC_000020.10:g.62070964AAG[1]
NC_000020.10:g.62070967_62070969delAAG
NC_000020.10:g.62070967_62070969delAAG
NM_172107.2:c.913_915delTTC
NM_172107.3:c.913_915delTTC
NM_172107.4:c.913_915delMANE SELECT
NM_172107.4:c.913_915delTTCMANE SELECT
NM_172109.2:c.913_915del

Protein change:

F305del

Links:

dbSNP: rs118192212

NCBI 1000 Genomes Browser:

rs118192212

Molecular consequence:

NM_001382235.1:c.910TTC[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_004518.6:c.910TTC[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_172106.3:c.910TTC[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_172107.4:c.910TTC[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_172108.5:c.910TTC[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_172109.3:c.910TTC[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Functional consequence:

Mild slowing of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0013]
Normal voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0032]
Severe decrease in peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0087]

Observations:

Condition(s)

Name:: KCNQ2-related disorder
Synonyms:: KCNQ2-related condition
Identifiers:: MedGen: CN169299

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002097296	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18640800, 22884718, 32214227, 28728838, 27602407, 25741868
SCV004710748	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (Jan 8, 2024)	germline	clinical testing
SCV005884372	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 26, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35723786, 18640800 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002097296

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 14, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004710748

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(Jan 8, 2024)

germline

clinical testing

SCV005884372

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 26, 2024)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

KCNQ2 abnormality in BECTS: benign childhood epilepsy with centrotemporal spikes following benign neonatal seizures resulting from a mutation of KCNQ2.

Ishii A, Miyajima T, Kurahashi H, Wang JW, Yasumoto S, Kaneko S, Hirose S.

Epilepsy Res. 2012 Nov;102(1-2):122-5. doi: 10.1016/j.eplepsyres.2012.07.011. Epub 2012 Aug 10.

PubMed [citation]

PMID:: 22884718

First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery.

Hengel H, Buchert R, Sturm M, Haack TB, Schelling Y, Mahajnah M, Sharkia R, Azem A, Balousha G, Ghanem Z, Falana M, Balousha O, Ayesh S, Keimer R, Deigendesch W, Zaidan J, Marzouqa H, Bauer P, Schöls L.

Eur J Hum Genet. 2020 Aug;28(8):1034-1043. doi: 10.1038/s41431-020-0609-9. Epub 2020 Mar 25. Erratum in: Eur J Hum Genet. 2022 Feb;30(2):248. doi: 10.1038/s41431-021-00909-7..

PubMed [citation]

PMID:: 32214227
PMCID:: PMC7382450

See all PubMed Citations (7)

Details of each submission

From DASA, SCV002097296.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 18640800) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:211236; PMID: 22884718; 32214227; 28728838; 27602407) - PS4. This variant is not present in population databases (rs118192212, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Protein length variants as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - PM4. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 32214227; 28728838) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.

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

From PreventionGenetics, part of Exact Sciences, SCV004710748.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The KCNQ2 c.913_915delTTC variant is predicted to result in an in-frame deletion (p.Phe305del). This variant was reported in multiple individuals with KCNQ2-related conditions including benign familial neonatal epilepsy (Ishii et al 2009. PubMed ID: 18640800; reported as p.Phe304del), early infantile epileptic encephalopathy (Hengel et al 2020. PubMed ID: 32214227; Table S1 in Bayat et al 2022. PubMed ID: 35723786; Millichap et al 2016. PubMed ID: 27602407; Table S1 in Vanoye et al 2022. PubMed ID: 35104249), and intellectual disability and developmental delay (Supplementary data in Bowling et al 2017. PubMed ID: 28554332). This variant has interpretations of likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/211236/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005884372.1

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

Description

Variant summary: KCNQ2 c.913_915delTTC (p.Phe305del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 250852 control chromosomes. c.913_915delTTC has been reported as de novo variant in the literature in individuals affected with KCNQ2-Related Disorders. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 35723786, 18640800). ClinVar contains an entry for this variant (Variation ID: 211236). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Apr 28, 2025

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