VCV001717297.5 - ClinVar

NM_172107.4(KCNQ2):c.715G>A (p.Gly239Ser)

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.

(3)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_172107.4(KCNQ2):c.715G>A (p.Gly239Ser)

Variation ID: 1717297 Accession: VCV001717297.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.33 20: 63442507 (GRCh38) [ NCBI UCSC ] 20: 62073860 (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	Nov 5, 2022	Mar 5, 2024	Jul 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_172107.4:c.715G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_742105.1:p.Gly239Ser	missense
NM_001382235.1:c.715G>A	NP_001369164.1:p.Gly239Ser	missense
NM_004518.5:c.715G>A
NM_004518.6:c.715G>A	NP_004509.2:p.Gly239Ser	missense
NM_172106.3:c.715G>A	NP_742104.1:p.Gly239Ser	missense
NM_172107.2:c.715G>A
NM_172108.5:c.715G>A	NP_742106.1:p.Gly239Ser	missense
NM_172109.3:c.715G>A	NP_742107.1:p.Gly239Ser	missense
NC_000020.11:g.63442507C>T
NC_000020.10:g.62073860C>T
NG_009004.2:g.35134G>A

... more HGVS ... less HGVS

Protein change

G239S

Other names

Canonical SPDI

NC_000020.11:63442506: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	2152	2283

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.
Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (1)	criteria provided, single submitter	Aug 21, 2022	RCV002297503.4
Developmental and epileptic encephalopathy, 7 Seizures, benign familial neonatal, 1	Likely pathogenic (1)	criteria provided, single submitter	-	RCV003883196.1
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 25, 2023	RCV003318716.1

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 (Jul 25, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004023026.1 First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); 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); Has not been previously reported in peer-reviewed literature as pathogenic or benign to our knowledge; however, in a preliminary report by Bayat et al. (2023), the variant was identified as de novo in two unrelated individuals with developmental delay, cognitive impairment, and autism spectrum disorder, and was suggested to have a gain of function effect; This variant is associated with the following publications: (PMID: 25959266, 34711204, 23692823, Bayat2023[functionalstudy]) (less)
Uncertain significance (Aug 21, 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: SCV002592876.3 First in ClinVar: Nov 05, 2022 Last updated: Feb 20, 2024	Comment: 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) … (more) 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 has not been reported in the literature in individuals affected with KCNQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 239 of the KCNQ2 protein (p.Gly239Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
likely Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 7 Seizures, benign familial neonatal, 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: de novo	Molecular Genetics Lab, CHRU Brest Accession: SCV004697587.1 First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); 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); Has not been previously reported in peer-reviewed literature as pathogenic or benign to our knowledge; however, in a preliminary report by Bayat et al. (2023), the variant was identified as de novo in two unrelated individuals with developmental delay, cognitive impairment, and autism spectrum disorder, and was suggested to have a gain of function effect; This variant is associated with the following publications: (PMID: 25959266, 34711204, 23692823, Bayat2023[functionalstudy])

Comment:

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 has not been reported in the literature in individuals affected with KCNQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 239 of the KCNQ2 protein (p.Gly239Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_172107.4(KCNQ2):c.715G>A (p.Gly239Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...