VCV000021768.17 - ClinVar

NM_172107.4(KCNQ2):c.1741C>T (p.Arg581Ter)

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.

(9)

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.1741C>T (p.Arg581Ter)

Variation ID: 21768 Accession: VCV000021768.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.33 20: 63413472 (GRCh38) [ NCBI UCSC ] 20: 62044825 (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	Aug 7, 2015	May 19, 2024	May 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_172107.4:c.1741C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_742105.1:p.Arg581Ter	nonsense
NM_004518.6:c.1657C>T	NP_004509.2:p.Arg553Ter	nonsense
NM_172106.3:c.1687C>T	NP_742104.1:p.Arg563Ter	nonsense
NM_172108.5:c.1648C>T	NP_742106.1:p.Arg550Ter	nonsense
NC_000020.11:g.63413472G>A
NC_000020.10:g.62044825G>A
NG_009004.2:g.64169C>T

... more HGVS ... less HGVS

Protein change

R581*, R550*, R553*, R563*

Other names

p.R581*:CGA>TGA

Canonical SPDI

NC_000020.11:63413471:G:A

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

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

dbSNP: rs118192236 ClinGen: CA315486 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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 7, 2022	RCV000187920.6
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Nov 15, 2023	RCV000636351.8
Seizures, benign familial neonatal, 1	Pathogenic (3)	criteria provided, single submitter	Jul 11, 2020	RCV000678061.7
KCNQ2-related disorder	Pathogenic (2)	criteria provided, single submitter	-	RCV003335050.2
Seizure	Pathogenic (1)	criteria provided, single submitter	May 14, 2024	RCV004554609.2

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 (Sep 03, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000241522.11 First in ClinVar: Aug 07, 2015 Last updated: Aug 07, 2015	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14534157, 25525159, 25982755, 26993267, 31199083) (less)
Pathogenic (Jul 11, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures, benign familial neonatal, 1 Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV001980686.1 First in ClinVar: Oct 21, 2021 Last updated: Oct 21, 2021	Comment: This nonsense variant found in exon 15 of 17 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated … (more) This nonsense variant found in exon 15 of 17 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in families with benign familial neonatal seizures (PMID: 14534157, 31199083, 26993267, 25982755). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.1741C>T (p.Arg581Ter) variant is classified as Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KCNQ2-Related Disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046328.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This nonsense variant found in exon 15 of 17 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated … (more) This nonsense variant found in exon 15 of 17 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change, predominantly inherited from an affected parent but also as a de novo change, in individuals with neonatal seizures (PMID: 14534157, 31199083, 26993267, 25982755, 19380078, 32863083, 34153113). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the maternal sample was negative for the c.1741C>T (p.Arg581Ter) variant. Based on the available evidence, the c.1741C>T (p.Arg581Ter) variant is classified as Pathogenic. (less)
Pathogenic (Jan 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003826515.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Nov 15, 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: SCV000757790.6 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 14534157‚ 23692823‚ 27779742‚ 25982755‚ 26993267 Comment: This sequence change creates a premature translational stop signal (p.Arg581) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg581) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157, 23692823, 27779742). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with benign familial neonatal seizures (PMID: 14534157, 25982755, 26993267). ClinVar contains an entry for this variant (Variation ID: 21768). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures Affected status: yes Allele origin: paternal	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV005043791.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Sex: male
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Seizures, benign familial neonatal, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001752421.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Sex: female
not provided (-)	no classification provided Method: phenotyping only	KCNQ2-related disorder Affected status: yes Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV004228791.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Comment: Variant interpreted as Pathogenic and reported on 01-31-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 01-31-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Seizure (present) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Gene Panel Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2021-01-31 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	Seizures, benign familial neonatal, 1 Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000041620.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 Comment: Functional effect: Slight rightward shift in current voltage-dependence; no effect on maximal current amplitude	Publications: PubMed (2) PubMed: 14534157‚ 25982755 BookShelf: NBK32534 BookShelf: NBK32534 Comment: BFNE (benign familial neonatal epilepsy)

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14534157, 25525159, 25982755, 26993267, 31199083)

Comment:

This nonsense variant found in exon 15 of 17 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in families with benign familial neonatal seizures (PMID: 14534157, 31199083, 26993267, 25982755). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.1741C>T (p.Arg581Ter) variant is classified as Pathogenic.

Comment:

This nonsense variant found in exon 15 of 17 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change, predominantly inherited from an affected parent but also as a de novo change, in individuals with neonatal seizures (PMID: 14534157, 31199083, 26993267, 25982755, 19380078, 32863083, 34153113). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the maternal sample was negative for the c.1741C>T (p.Arg581Ter) variant. Based on the available evidence, the c.1741C>T (p.Arg581Ter) variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg581*) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157, 23692823, 27779742). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with benign familial neonatal seizures (PMID: 14534157, 25982755, 26993267). ClinVar contains an entry for this variant (Variation ID: 21768). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 01-31-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

This nonsense variant found in exon 15 of 17 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change, predominantly inherited from an affected parent but also as a de novo change, in individuals with neonatal seizures (PMID: 14534157, 31199083, 26993267, 25982755, 19380078, 32863083, 34153113). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the maternal sample was negative for the c.1741C>T (p.Arg581Ter) variant. Based on the available evidence, the c.1741C>T (p.Arg581Ter) variant is classified as Pathogenic.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
KCNQ2-Related Disorders.	Adam MP	-	2022	PMID: 20437616
Gene mutation analysis of 175 Chinese patients with early-onset epileptic encephalopathy.	Zhang Q	Clinical genetics	2017	PMID: 27779742
Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis.	Trump N	Journal of medical genetics	2016	PMID: 26993267
Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome.	Grinton BE	Epilepsia	2015	PMID: 25982755
Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2.	Milh M	Orphanet journal of rare diseases	2013	PMID: 23692823
KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum.	Singh NA	Brain : a journal of neurology	2003	PMID: 14534157

Text-mined citations for rs118192236 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_172107.4(KCNQ2):c.1741C>T (p.Arg581Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs118192236 ...