VCV000211236.55 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 211236 Accession: VCV000211236.55

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 20q13.33 20: 63439610-63439612 (GRCh38) [ NCBI UCSC ] 20: 62070963-62070965 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 5, 2015	Oct 20, 2024	Jul 3, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_172107.4:c.910TTC[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_742105.1:p.Phe305del	inframe deletion
NM_172107.4:c.913_915del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_172107.4:c.913_915delTTC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001382235.1:c.910TTC[1]	NP_001369164.1:p.Phe305del	inframe deletion
NM_004518.6:c.910TTC[1]	NP_004509.2:p.Phe305del	inframe deletion
NM_172106.3:c.910TTC[1]	NP_742104.1:p.Phe305del	inframe deletion
NM_172107.2:c.913_915delTTC
NM_172107.3:c.913_915delTTC
NM_172108.5:c.910TTC[1]	NP_742106.1:p.Phe305del	inframe deletion
NM_172109.3:c.910TTC[1]	NP_742107.1:p.Phe305del	inframe deletion
NC_000020.11:g.63439611AAG[1]
NC_000020.10:g.62070964AAG[1]
NG_009004.2:g.38026TTC[1]

... more HGVS ... less HGVS

Protein change

F305del

Other names

F304delF

Canonical SPDI

NC_000020.11:63439609:GAAGAAG:GAAG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA208154 dbSNP: rs118192212 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
KCNQ2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	2156	2287

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Developmental and epileptic encephalopathy, 7	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 16, 2021	RCV000234792.7
Seizure	Pathogenic (1)	criteria provided, single submitter	Jun 26, 2015	RCV000194164.7
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 5, 2022	RCV000414259.28
not specified	Pathogenic (1)	criteria provided, single submitter	Dec 15, 2018	RCV001002283.9
Benign Rolandic epilepsy	not provided (1)	no classification provided	-	RCV000678098.5
Seizures, benign familial neonatal, 1	Pathogenic (1)	criteria provided, single submitter	Nov 10, 2021	RCV000990332.4
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Jul 3, 2023	RCV001381685.7
KCNQ2-related disorder	Pathogenic (2)	criteria provided, single submitter	Feb 14, 2022	RCV001836639.6
Complex neurodevelopmental disorder	not provided (1)	no classification provided	-	RCV003315329.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 26, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000247668.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Pathogenic (Dec 15, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001160166.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Comment: De novo occurrence of the p.Phe305del variant has been reported in several individuals (Ishii 2009, Millichap 2016, Sterbova 2017, Bowling 2017, Spagnoli 2018) including identical … (more) De novo occurrence of the p.Phe305del variant has been reported in several individuals (Ishii 2009, Millichap 2016, Sterbova 2017, Bowling 2017, Spagnoli 2018) including identical twins (Millichap 2016). This variant is absent from general population databases including gnomAD but is listed in ClinVar with pathogenic classification (ClinVar ID 211236). The p.Phe305del variant is located in the Kv7.2 channel transmembrane segment 6, in the ion transport domain (IPR005821). Ishii et al. (2009) showed that this variant (reported as Phe304del) leads to null function with no current observed in the mutant KCNQ2 potassium channel. Based on the available evidence, this de novo p.Phe305del KCNQ2 gene variant was classified as pathogenic. (less)
Pathogenic (Nov 10, 2021)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Seizures, benign familial neonatal, 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001141275.2 First in ClinVar: Jan 09, 2020 Last updated: Nov 13, 2021
Pathogenic (Feb 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KCNQ2-related disorder Affected status: yes Allele origin: germline	DASA Accession: SCV002097296.1 First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022	Publications: PubMed (5) PubMed: 18640800‚ 22884718‚ 32214227‚ 28728838‚ 27602407 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Sex: male Geographic origin: Uruaguay
Likely pathogenic (Nov 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 7 Affected status: yes Allele origin: de novo	Pediatrics, West China Second University Hospital, Sichuan University Accession: SCV002525867.1 First in ClinVar: Jun 18, 2022 Last updated: Jun 18, 2022
Pathogenic (Jun 09, 2016)	criteria provided, single submitter (HA_assertions_20161101) Method: research	Developmental and epileptic encephalopathy, 7 Affected status: yes Allele origin: de novo	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-HudsonAlpha Accession: SCV000291976.4 First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Delayed speech and language development (present) , Hypertonia (present) , Cortical visual impairment (present)
Pathogenic (Aug 05, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491167.4 First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect and significant impairment of potassium channel function (Ishii et al., 2009); Not observed at significant frequency in large … (more) Published functional studies demonstrate a damaging effect and significant impairment of potassium channel function (Ishii et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; Lost residue is predicted to be within the transmembrane segment S6; This variant is associated with the following publications: (PMID: 20437616, 18640800, 27602407, 28554332, 28728838, 32214227, 35401395) (less)
Pathogenic (Jul 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Early infantile epileptic encephalopathy with suppression bursts Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001580178.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 25473036‚ 18640800‚ 27602407‚ 28728838 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe305 amino acid residue in KCNQ2. Other variant(s) that disrupt this … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe305 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25473036; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this variant affects KCNQ2 function (PMID: 18640800). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 211236). This variant is also known as c.910-2delTTC. This variant has been observed in individual(s) with KCNQ2-related conditions (PMID: 18640800, 27602407, 28728838). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.913_915del, results in the deletion of 1 amino acid(s) of the KCNQ2 protein (p.Phe305del), but otherwise preserves the integrity of the reading frame. (less)
Pathogenic (Sep 01, 2016)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247382.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Likely pathogenic (Aug 01, 2019)	no assertion criteria provided Method: research	Developmental and epileptic encephalopathy, 7 Affected status: yes Allele origin: germline	Section for Clinical Neurogenetics, University of Tübingen Accession: SCV001156087.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (1) PubMed: 32214227
Pathogenic (Jan 08, 2024)	no assertion criteria provided Method: clinical testing	KCNQ2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004710748.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
not provided (-)	no classification provided Method: literature only	Benign Rolandic epilepsy Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000041663.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 Comment: Functional effect: Lack of functional homomeric channels	Publications: PubMed (2) PubMed: 18640800‚ 22884718 BookShelf: NBK32534 BookShelf: NBK32534 Comment: BECTS (benign childhood epilepsy with centrotemporal spikes)
not provided (-)	no classification provided Method: literature only	Complex neurodevelopmental disorder Affected status: not applicable Allele origin: not applicable	Channelopathy-Associated Epilepsy Research Center Accession: SCV004015101.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (1) PubMed: 35104249 Method: whole-cell patch-clamp recording Result: Severe decrease in peak current;Mild slowing of activation;Normal voltage dependence of activation
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Comment:

De novo occurrence of the p.Phe305del variant has been reported in several individuals (Ishii 2009, Millichap 2016, Sterbova 2017, Bowling 2017, Spagnoli 2018) including identical twins (Millichap 2016). This variant is absent from general population databases including gnomAD but is listed in ClinVar with pathogenic classification (ClinVar ID 211236). The p.Phe305del variant is located in the Kv7.2 channel transmembrane segment 6, in the ion transport domain (IPR005821). Ishii et al. (2009) showed that this variant (reported as Phe304del) leads to null function with no current observed in the mutant KCNQ2 potassium channel. Based on the available evidence, this de novo p.Phe305del KCNQ2 gene variant was classified as pathogenic.

Comment:

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.

Comment:

Published functional studies demonstrate a damaging effect and significant impairment of potassium channel function (Ishii et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; Lost residue is predicted to be within the transmembrane segment S6; This variant is associated with the following publications: (PMID: 20437616, 18640800, 27602407, 28554332, 28728838, 32214227, 35401395)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe305 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25473036; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this variant affects KCNQ2 function (PMID: 18640800). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 211236). This variant is also known as c.910-2delTTC. This variant has been observed in individual(s) with KCNQ2-related conditions (PMID: 18640800, 27602407, 28728838). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.913_915del, results in the deletion of 1 amino acid(s) of the KCNQ2 protein (p.Phe305del), but otherwise preserves the integrity of the reading frame.

Comment:

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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Severe decrease in peak current (FENICS-0087) Mild slowing of activation (FENICS-0013) Normal voltage dependence of activation (FENICS-0032)	whole-cell patch-clamp recording	Severe decrease in peak current;Mild slowing of activation;Normal voltage dependence of activation	Channelopathy-Associated Epilepsy Research Center Accession: SCV004015101.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity.	Vanoye CG	JCI insight	2022	PMID: 35104249
KCNQ2-Related Disorders.	Adam MP	-	2022	PMID: 20437616
First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery.	Hengel H	European journal of human genetics : EJHG	2020	PMID: 32214227
KCNQ2 encephalopathy: A case due to a de novo deletion.	Spagnoli C	Brain & development	2018	PMID: 28728838
KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients.	Millichap JJ	Neurology. Genetics	2016	PMID: 27602407
Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.	Soden SE	Science translational medicine	2014	PMID: 25473036
KCNQ2 abnormality in BECTS: benign childhood epilepsy with centrotemporal spikes following benign neonatal seizures resulting from a mutation of KCNQ2.	Ishii A	Epilepsy research	2012	PMID: 22884718
A de novo KCNQ2 mutation detected in non-familial benign neonatal convulsions.	Ishii A	Brain & development	2009	PMID: 18640800

Text-mined citations for rs118192212 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs118192212 ...