VCV000021417.10 - ClinVar

NM_004519.4(KCNQ3):c.988C>T (p.Arg330Cys)

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.

(7)

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_004519.4(KCNQ3):c.988C>T (p.Arg330Cys)

Variation ID: 21417 Accession: VCV000021417.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q24.22 8: 132174295 (GRCh38) [ NCBI UCSC ] 8: 133186542 (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	Jul 27, 2015	Feb 28, 2024	May 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004519.4:c.988C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004510.1:p.Arg330Cys	missense
NM_001204824.2:c.628C>T	NP_001191753.1:p.Arg210Cys	missense
NC_000008.11:g.132174295G>A
NC_000008.10:g.133186542G>A
NG_008854.2:g.311463C>T

... more HGVS ... less HGVS

Protein change

R330C, R210C

Other names

Canonical SPDI

NC_000008.11:132174294: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.

Links

ClinGen: CA342043 OMIM: 602232.0003 dbSNP: rs118192251 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.
KCNQ3		-	-	GRCh38 GRCh37	1328	1399

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, 2	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 2, 2021	RCV000020602.9
Benign neonatal seizures	Pathogenic (1)	criteria provided, single submitter	May 15, 2023	RCV000462450.5
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 5, 2022	RCV003233074.1

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.
Likely pathogenic (Oct 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures, benign familial neonatal, 2 Affected status: yes Allele origin: unknown	3billion Accession: SCV002012197.1 First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021	Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23146207, PS1). It is not … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23146207, PS1). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.973, 3Cnet: 0.981, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Autistic behavior (present) , Delayed speech and language development (present) , Motor delay (present) , Global developmental delay (present)
Pathogenic (Dec 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: SCV003931034.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Comment: Published functional studies demonstrate abnormal channel function (Miceli et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein … (more) Published functional studies demonstrate abnormal channel function (Miceli et al., 2015); 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: 23146207, 16883520, 28717674, 35627257, 34474328, 18249525, 25524373, 34136434) (less)
Pathogenic (Oct 08, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Seizures, benign familial neonatal, 2 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743523.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (May 15, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Benign neonatal seizures Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000543210.5 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 18249525‚ 23146207 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ3 protein function. ClinVar contains an entry for this variant (Variation ID: 21417). This missense change has been observed in individuals with benign familial neonatal seizures (PMID: 18249525, 23146207). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 330 of the KCNQ3 protein (p.Arg330Cys). (less)
Pathogenic (May 01, 2013)	no assertion criteria provided Method: literature only	SEIZURES, BENIGN FAMILIAL NEONATAL, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000121585.2 First in ClinVar: Mar 20, 2014 Last updated: Jul 27, 2015	Publications: PubMed (2) PubMed: 18249525‚ 23146207 Comment on evidence: In affected members of a Chinese family with benign neonatal seizures-2 (BFNS2; 121201), Li et al. (2008) identified a heterozygous c.988C-T transition in exon 6 … (more) In affected members of a Chinese family with benign neonatal seizures-2 (BFNS2; 121201), Li et al. (2008) identified a heterozygous c.988C-T transition in exon 6 of the KCNQ3 gene, resulting in an arg330-to-cys (R330C) substitution at a highly conserved residue in the linker domain of the pore region and S6. The mutation, which was found by linkage analysis followed by candidate gene sequencing, segregated with the disorder in the family. It was not present in 100 control individuals. Functional studies were not performed. Affected individuals developed afebrile partial clonic seizures on the second or third day of life, which remitted in all patients by 1 month of age. There was no later recurrence of seizures, and all showed normal psychomotor development. Fister et al. (2013) identified a heterozygous R330C substitution in a Slovenian mother and daughter with BFNS2. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Seizures, benign familial neonatal, 2 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734592.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
not provided (-)	no classification provided Method: literature only	Seizures, benign familial neonatal, 2 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000041091.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (4) PubMed: 16883520‚ 18249525‚ 23146207‚ 25524373 BookShelf: NBK201978 BookShelf: NBK201978 Comment: Same variant detected in 2 unrelated families

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23146207, PS1). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.973, 3Cnet: 0.981, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Published functional studies demonstrate abnormal channel function (Miceli et al., 2015); 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: 23146207, 16883520, 28717674, 35627257, 34474328, 18249525, 25524373, 34136434)

Comment:

For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ3 protein function. ClinVar contains an entry for this variant (Variation ID: 21417). This missense change has been observed in individuals with benign familial neonatal seizures (PMID: 18249525, 23146207). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 330 of the KCNQ3 protein (p.Arg330Cys).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
KCNQ3-Related Disorders.	Adam MP	-	2023	PMID: 24851285
KCNQ2-Related Disorders.	Adam MP	-	2022	PMID: 20437616
A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability.	Miceli F	Epilepsia	2015	PMID: 25524373
Benign familial neonatal convulsions caused by mutation in KCNQ3, exon 6: a European case.	Fister P	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2013	PMID: 23146207
A novel mutation of KCNQ3 gene in a Chinese family with benign familial neonatal convulsions.	Li H	Epilepsy research	2008	PMID: 18249525
[Clinical and mutational analysis of KCNQ3 gene in a Chinese family with benign familial neonatal convulsions].	Li HY	Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics	2006	PMID: 16883520

Text-mined citations for rs118192251 ...

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_004519.4(KCNQ3):c.988C>T (p.Arg330Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs118192251 ...