VCV002507190.2 - ClinVar

NM_172107.4(KCNQ2):c.1955del (p.Pro652fs)

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.

(2)

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.1955del (p.Pro652fs)

Variation ID: 2507190 Accession: VCV002507190.2

Type and length

Deletion, 1 bp

Location

Cytogenetic: 20q13.33 20: 63407308 (GRCh38) [ NCBI UCSC ] 20: 62038661 (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 8, 2023	Feb 28, 2024	Jan 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_172107.4:c.1955del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_742105.1:p.Pro652fs	frameshift
NM_001382235.1:c.2009del	NP_001369164.1:p.Pro670fs	frameshift
NM_004518.6:c.1871del	NP_004509.2:p.Pro624fs	frameshift
NM_172106.3:c.1901del	NP_742104.1:p.Pro634fs	frameshift
NM_172108.5:c.1862del	NP_742106.1:p.Pro621fs	frameshift
NC_000020.11:g.63407313del
NC_000020.10:g.62038666del
NG_009004.2:g.70333del

... more HGVS ... less HGVS

Protein change

P621fs, P624fs, P634fs, P652fs, P670fs

Other names

Canonical SPDI

NC_000020.11:63407307:GGGGGG:GGGGG

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	Pathogenic (1)	criteria provided, single submitter	Jan 10, 2024	RCV003779868.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jul 3, 2023	RCV003239081.1

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 (Jul 03, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003936419.1 First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023	Comment: Reported in the published literature (Goto et al., 2019) in a patient with benign (familial) neonatal epilepsy, though without specific segregation details provided; Frameshift variant … (more) Reported in the published literature (Goto et al., 2019) in a patient with benign (familial) neonatal epilepsy, though without specific segregation details provided; Frameshift variant predicted to result in protein truncation, as the last 221 amino acids are replaced with 277 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); The lost residues are within C-terminal cytoplasmic domain; This variant is associated with the following publications: (PMID: 31418850) (less)
Pathogenic (Jan 10, 2024)	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: SCV004631141.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 31418850‚ 14534157 Comment: This sequence change results in a frameshift in the KCNQ2 gene (p.Pro652Argfs278). While this is not anticipated to result in nonsense mediated decay, it is … (more) This sequence change results in a frameshift in the KCNQ2 gene (p.Pro652Argfs278). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 221 amino acid(s) of the KCNQ2 protein and extend the protein by 56 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with benign familial neonatal epilepsy (PMID: 31418850). ClinVar contains an entry for this variant (Variation ID: 2507190). This variant results in an extension of the KCNQ2 protein. Other variant(s) that result in a similarly extended protein product (c.1956del) have been determined to be pathogenic (PMID: 14534157; Invitae). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

Reported in the published literature (Goto et al., 2019) in a patient with benign (familial) neonatal epilepsy, though without specific segregation details provided; Frameshift variant predicted to result in protein truncation, as the last 221 amino acids are replaced with 277 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); The lost residues are within C-terminal cytoplasmic domain; This variant is associated with the following publications: (PMID: 31418850)

Comment:

This sequence change results in a frameshift in the KCNQ2 gene (p.Pro652Argfs*278). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 221 amino acid(s) of the KCNQ2 protein and extend the protein by 56 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with benign familial neonatal epilepsy (PMID: 31418850). ClinVar contains an entry for this variant (Variation ID: 2507190). This variant results in an extension of the KCNQ2 protein. Other variant(s) that result in a similarly extended protein product (c.1956del) have been determined to be pathogenic (PMID: 14534157; Invitae). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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
Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy.	Goto A	Epilepsia	2019	PMID: 31418850
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 this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_172107.4(KCNQ2):c.1955del (p.Pro652fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...