VCV000007391.17 - ClinVar

NM_172107.4(KCNQ2):c.620G>A (p.Arg207Gln)

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.

(8)

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

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.620G>A (p.Arg207Gln)

Variation ID: 7391 Accession: VCV000007391.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.33 20: 63444729 (GRCh38) [ NCBI UCSC ] 20: 62076082 (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	Apr 4, 2013	Oct 8, 2024	Feb 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_172107.4:c.620G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_742105.1:p.Arg207Gln	missense
NM_004518.6:c.620G>A	NP_004509.2:p.Arg207Gln	missense
NM_172106.3:c.620G>A	NP_742104.1:p.Arg207Gln	missense
NM_172108.5:c.620G>A	NP_742106.1:p.Arg207Gln	missense
NM_172109.3:c.620G>A	NP_742107.1:p.Arg207Gln	missense
NC_000020.11:g.63444729C>T
NC_000020.10:g.62076082C>T
NG_009004.2:g.32912G>A
	O43526:p.Arg207Gln

... more HGVS ... less HGVS

Protein change

R207Q

Other names

p.R207Q:CGG>CAG

Canonical SPDI

NC_000020.11:63444728:C:T

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

Normal peak current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0096]

Severe depolarizing shift of voltage dependence of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0026]

Severe slowing of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0015]

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: CA118745 UniProtKB: O43526#VAR_043819 OMIM: 602235.0011 dbSNP: rs118192200 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	2148	2279

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.
Seizures, benign familial neonatal, 1, and/or myokymia	Pathogenic (1)	no assertion criteria provided	Nov 27, 2007	RCV000007815.3
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 31, 2022	RCV000187863.6
Developmental and epileptic encephalopathy, 7	not provided (1)	no classification provided	-	RCV000678085.4
Developmental and epileptic encephalopathy, 7 Seizures, benign familial neonatal, 1	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763453.3
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Feb 18, 2023	RCV001205287.9
Complex neurodevelopmental disorder	not provided (1)	no classification provided	-	RCV003315294.1
KCNQ2-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 5, 2024	RCV004732533.1

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 (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures, benign familial neonatal, 1 Developmental and epileptic encephalopathy, 7 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894229.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Oct 31, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000241463.15 First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023	Comment: Previously reported in an individual with myokymia due to peripheral nerve hyperexcitability, and functional studies indicate this variant alters voltage-dependent activation (Wuttke et al., 2007; … (more) Previously reported in an individual with myokymia due to peripheral nerve hyperexcitability, and functional studies indicate this variant alters voltage-dependent activation (Wuttke et al., 2007; Miceli et al., 2012); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17872363, 29655203, 22455920, 32184343, 25959266, 25741868, 24375629, 22169383, 11572947, 32884139, 32506321, 33098118) (less)
Pathogenic (Jan 08, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001144319.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (2) PubMed: 25959266‚ 17872363 Comment: Not found in the total gnomAD dataset, and the data is high quality (0/270462 chr). Predicted to have a damaging effect on the protein. One … (more) Not found in the total gnomAD dataset, and the data is high quality (0/270462 chr). Predicted to have a damaging effect on the protein. One de novo case with parental identity confirmed. (less)
Pathogenic (Feb 18, 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: SCV001376533.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 17872363‚ 25959266‚ 29655203‚ 32184343‚ 34711204‚ 22455920‚ 11572947‚ 22169383‚ 24375629 Comment: For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral … (more) For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the KCNQ2 protein (p.Arg207Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 17872363, 25959266, 29655203, 32184343, 34711204). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7391). 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. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 17872363, 22455920). This variant disrupts the p.Arg207 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11572947, 22169383, 22455920, 24375629). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. (less)
Pathogenic (Nov 27, 2007)	no assertion criteria provided Method: literature only	SEIZURES, BENIGN FAMILIAL NEONATAL, 1, AND/OR MYOKYMIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028020.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 17872363 Comment on evidence: In a 25-year-old Egyptian man with isolated myokymia (see 121200), Wuttke et al. (2007) identified a heterozygous G-to-A transition in the KCNQ2 gene, resulting in … (more) In a 25-year-old Egyptian man with isolated myokymia (see 121200), Wuttke et al. (2007) identified a heterozygous G-to-A transition in the KCNQ2 gene, resulting in an arg207-to-gln (R207Q) substitution in a highly conserved residue in the voltage sensor region of the potassium channel. He had no history of neonatal seizures and no family history of epilepsy or peripheral nerve hyperexcitability. Clinically, he had permanent muscle overactivity in the distal upper extremities and small amplitude movements of the fingers, which were not disabling. However, he also reported exercise-induced cramps of both hands since childhood and 4 episodes of exercise-induced generalized muscle stiffness. EMG showed spontaneous irregular discharges consistent with myokymia. Wuttke et al. (2007) noted that a mutation in the same codon (R207W; 602235.0006) had been associated with neonatal epilepsy and/or myokymia. In vitro functional expression studies showed that mutant R207W and R207Q channels had large depolarizing shifts and marked slowing of activation time compared to wildtype channels. Coexpression with wildtype channels showed a dominant-negative effect reducing the current amplitude by 70% after short depolarization. (less)
Pathogenic (Aug 05, 2024)	no assertion criteria provided Method: clinical testing	KCNQ2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005367684.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The KCNQ2 c.620G>A variant is predicted to result in the amino acid substitution p.Arg207Gln. This variant has been reported in several individuals with KCNQ2-related phenotypes … (more) The KCNQ2 c.620G>A variant is predicted to result in the amino acid substitution p.Arg207Gln. This variant has been reported in several individuals with KCNQ2-related phenotypes (Wuttke et al 2007. PubMed ID: 17872363; Lindy AS et al 2018. PubMed ID: 29655203; Camelo CG et al 2020. PubMed ID: 32184343; Sandoval Karamian AG et al 2020. PubMed ID: 33098118). This variant has not been reported in a large population database, indicating it is rare. This variant modifies a charged residue in the ion channel S4 voltage sensor. Variants of this type, including a different missense variant at the same position (p.Arg207Trp), have been associated with disease (Dedek et al. 2001. PubMed ID: 11572947), and both p.Arg207 missense variants change the biochemical properties of the ion channel in vitro (Miceli F et al 2012. PubMed ID: 22455920). Taken together, the c.620G>A (p.Arg207Gln) variant is interpreted as pathogenic. (less)
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: SCV004015066.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (1) PubMed: 35104249 Method: whole-cell patch-clamp recording Result: Normal peak current;Severe slowing of activation;Severe depolarizing shift of voltage dependence of activation
not provided (-)	no classification provided Method: literature only	Developmental and epileptic encephalopathy, 7 Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000041646.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 Comment: Functional effect: Rightward shift in current voltage-dependence; decrease in current activation kinetics	Publications: PubMed (2) PubMed: 17872363‚ 25959266 BookShelf: NBK32534 BookShelf: NBK32534 Comment: Myokymia, EE (epileptic encephalopathy)

Comment:

Previously reported in an individual with myokymia due to peripheral nerve hyperexcitability, and functional studies indicate this variant alters voltage-dependent activation (Wuttke et al., 2007; Miceli et al., 2012); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17872363, 29655203, 22455920, 32184343, 25959266, 25741868, 24375629, 22169383, 11572947, 32884139, 32506321, 33098118)

Comment:

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the KCNQ2 protein (p.Arg207Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 17872363, 25959266, 29655203, 32184343, 34711204). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7391). 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. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 17872363, 22455920). This variant disrupts the p.Arg207 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11572947, 22169383, 22455920, 24375629). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

Comment:

The KCNQ2 c.620G>A variant is predicted to result in the amino acid substitution p.Arg207Gln. This variant has been reported in several individuals with KCNQ2-related phenotypes (Wuttke et al 2007. PubMed ID: 17872363; Lindy AS et al 2018. PubMed ID: 29655203; Camelo CG et al 2020. PubMed ID: 32184343; Sandoval Karamian AG et al 2020. PubMed ID: 33098118). This variant has not been reported in a large population database, indicating it is rare. This variant modifies a charged residue in the ion channel S4 voltage sensor. Variants of this type, including a different missense variant at the same position (p.Arg207Trp), have been associated with disease (Dedek et al. 2001. PubMed ID: 11572947), and both p.Arg207 missense variants change the biochemical properties of the ion channel in vitro (Miceli F et al 2012. PubMed ID: 22455920). Taken together, the c.620G>A (p.Arg207Gln) 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.
Normal peak current (FENICS-0096) Severe slowing of activation (FENICS-0015) Severe depolarizing shift of voltage dependence of activation (FENICS-0026)	whole-cell patch-clamp recording	Normal peak current;Severe slowing of activation;Severe depolarizing shift of voltage dependence of activation	Channelopathy-Associated Epilepsy Research Center Accession: SCV004015066.1	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
Early initial video-electro-encephalography combined with variant location predict prognosis of KCNQ2-related disorder.	Xu Y	BMC pediatrics	2021	PMID: 34711204
Facial myokymia in inherited peripheral nerve hyperexcitability syndrome.	Camelo CG	Practical neurology	2020	PMID: 32184343
Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.	Lindy AS	Epilepsia	2018	PMID: 29655203
Variable clinical expression in patients with mosaicism for KCNQ2 mutations.	Milh M	American journal of medical genetics. Part A	2015	PMID: 25959266
Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.	Soldovieri MV	Human mutation	2014	PMID: 24375629
Gating currents from Kv7 channels carrying neuronal hyperexcitability mutations in the voltage-sensing domain.	Miceli F	Biophysical journal	2012	PMID: 22455920
Neonatal seizures associated with a severe neonatal myoclonus like dyskinesia due to a familial KCNQ2 gene mutation.	Blumkin L	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2012	PMID: 22169383
Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations.	Wuttke TV	Neurology	2007	PMID: 17872363
Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel.	Dedek K	Proceedings of the National Academy of Sciences of the United States of America	2001	PMID: 11572947
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Text-mined citations for rs118192200 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_172107.4(KCNQ2):c.620G>A (p.Arg207Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs118192200 ...