VCV002584390.11 - ClinVar

NM_172107.4(KCNQ2):c.937G>A (p.Gly313Arg)

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.

(4)

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.937G>A (p.Gly313Arg)

Variation ID: 2584390 Accession: VCV002584390.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.33 20: 63438711 (GRCh38) [ NCBI UCSC ] 20: 62070064 (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 21, 2023	Oct 20, 2024	Jan 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_172107.4:c.937G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_742105.1:p.Gly313Arg	missense
NM_001382235.1:c.937G>A	NP_001369164.1:p.Gly313Arg	missense
NM_004518.6:c.937G>A	NP_004509.2:p.Gly313Arg	missense
NM_172106.3:c.937G>A	NP_742104.1:p.Gly313Arg	missense
NM_172107.2:c.937G>A
NM_172108.5:c.937G>A	NP_742106.1:p.Gly313Arg	missense
NM_172109.3:c.937G>A	NP_742107.1:p.Gly313Arg	missense
NC_000020.11:g.63438711C>T
NC_000020.10:g.62070064C>T
NG_009004.2:g.38930G>A

... more HGVS ... less HGVS

Protein change

G313R

Other names

Canonical SPDI

NC_000020.11:63438710:C:T

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

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 (1)	criteria provided, single submitter	Aug 30, 2022	RCV003335838.4
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Dec 12, 2022	RCV003588892.2
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 1, 2024	RCV003886622.9

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 (Aug 30, 2022)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Developmental and epileptic encephalopathy, 7 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV004045971.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Number of individuals with the variant: 1 Clinical Features: Dysphagia (present) , Spasticity (present) , Cerebral palsy (present) , Global developmental delay (present) , Hypotonia (present) , Seizure (present)
Pathogenic (Dec 12, 2022)	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: SCV004297360.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 35377796‚ 28133863 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly313 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.Gly313 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (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 missense change affects KCNQ2 function (PMID: 35377796). 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. This variant is also known as Kv7.2 G1R. This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 28133863). 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 sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 313 of the KCNQ2 protein (p.Gly313Arg). (less)
Pathogenic (Sep 01, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005326268.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Published functional studies demonstrate a damaging effect with a dominant negative mechanism (Nappi et al., 2022); In silico analysis supports that this missense variant has … (more) Published functional studies demonstrate a damaging effect with a dominant negative mechanism (Nappi et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the C-terminal cytoplasmic domain; This variant is associated with the following publications: (PMID: 28133863, 35377796) (less)
Likely pathogenic (Jan 01, 2024)	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: SCV004702277.8 First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024	Comment: KCNQ2: PM1, PM2, PM6:Supporting, PP2, PP3, PS3:Supporting, PS4:Supporting Number of individuals with the variant: 1

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly313 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (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 missense change affects KCNQ2 function (PMID: 35377796). 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. This variant is also known as Kv7.2 G1R. This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 28133863). 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 sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 313 of the KCNQ2 protein (p.Gly313Arg).

Comment:

Published functional studies demonstrate a damaging effect with a dominant negative mechanism (Nappi et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the C-terminal cytoplasmic domain; This variant is associated with the following publications: (PMID: 28133863, 35377796)

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
Gain of function due to increased opening probability by two KCNQ5 pore variants causing developmental and epileptic encephalopathy.	Nappi M	Proceedings of the National Academy of Sciences of the United States of America	2022	PMID: 35377796
Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression.	Olson HE	Annals of neurology	2017	PMID: 28133863

Text-mined citations for this variant ...

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_172107.4(KCNQ2):c.937G>A (p.Gly313Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...