VCV000461213.5 - ClinVar

NC_000020.11:g.(?_63444639)_(63528152_?)del

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.

Conflicting classifications of pathogenicity
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

NC_000020.11:g.(?_63444639)_(63528152_?)del

Variation ID: 461213 Accession: VCV000461213.5

Type and length

Deletion, 83,514 bp

Location

Cytogenetic: 20q13.33 20: 63444639-63528152 (GRCh38) [ NCBI UCSC ] 20: 62075992-62159505 (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	Dec 26, 2017	Jun 29, 2024	Jan 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NC_000020.11:g.(?_63444639)_(63528152_?)del
NC_000020.10:g.(?_62075992)_(62159505_?)del

Protein change

Other names

Canonical SPDI

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
EEF1A2		No evidence available	No evidence available	GRCh38 GRCh37	506	667
KCNQ2-AS1	-	-	-	GRCh38	-	28
LOC129391211	-	-	-	GRCh38 GRCh38	-	28
LOC129391212	-	-	-	GRCh38	-	27
LOC130066357	-	-	-	GRCh38	-	24
LOC132090595	-	-	-	GRCh38	-	86
LOC132090596	-	-	-	GRCh38	-	27
PPDPF	-	-	-	GRCh38 GRCh37	16	104
PTK6		-	-	GRCh38 GRCh37	46	127

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	Jul 2, 2019	RCV000549284.5
Developmental and epileptic encephalopathy, 33	Uncertain significance (1)	criteria provided, single submitter	Jan 15, 2024	RCV004579552.2

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 (Jul 02, 2019)	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: SCV000633755.3 First in ClinVar: Dec 26, 2017 Last updated: Apr 09, 2020	Publications: PubMed (1) PubMed: 19822871 Comment: This variant is a gross deletion of the genomic region encompassing exons 1-4 of the KCNQ2 gene, which includes the initiator codon. The 5' end … (more) This variant is a gross deletion of the genomic region encompassing exons 1-4 of the KCNQ2 gene, which includes the initiator codon. The 5' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. The 3' boundary is likely confined to intron 4 of the KCNQ2 gene. This is expected to result in an absent or disrupted protein product. A deletion encompassing exons 1-4 of KCNQ2, as well as several upstream genes, has been reported in a family affected with benign familial neonatal seizures (PMID: 19822871). Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157). For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (Jan 15, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy, 33 Affected status: unknown Allele origin: unknown	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005063487.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Publications: PubMed (4) PubMed: 17290276‚ 20805988‚ 23166088‚ 26030193 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the EEF1A2 gene has been identified. The current clinical and genetic evidence … (more) A gross deletion of the genomic region encompassing the full coding sequence of the EEF1A2 gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in EEF1A2 cause disease. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of EEF1A2 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 17290276, 20805988, 23166088, 26030193). 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)

Comment:

This variant is a gross deletion of the genomic region encompassing exons 1-4 of the KCNQ2 gene, which includes the initiator codon. The 5' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. The 3' boundary is likely confined to intron 4 of the KCNQ2 gene. This is expected to result in an absent or disrupted protein product. A deletion encompassing exons 1-4 of KCNQ2, as well as several upstream genes, has been reported in a family affected with benign familial neonatal seizures (PMID: 19822871). Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157). For these reasons, this variant has been classified as Pathogenic.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the EEF1A2 gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in EEF1A2 cause disease. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of EEF1A2 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 17290276, 20805988, 23166088, 26030193). 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

Title	Author	Journal	Year	Link
Phenotypes of children with 20q13.3 microdeletion affecting KCNQ2 and CHRNA4.	Okumura A	Epileptic disorders : international epilepsy journal with videotape	2015	PMID: 26030193
Epilepsy due to 20q13.33 subtelomere deletion masquerading as pyridoxine-dependent epilepsy.	Mefford HC	American journal of medical genetics. Part A	2012	PMID: 23166088
A genotype-first approach for the molecular and clinical characterization of uncommon de novo microdeletion of 20q13.33.	Traylor RN	PloS one	2010	PMID: 20805988
Deletions involving both KCNQ2 and CHRNA4 present with benign familial neonatal seizures.	Kurahashi H	Neurology	2009	PMID: 19822871
Genotype-phenotype correlations to aid in the prognosis of individuals with uncommon 20q13.33 subtelomere deletions: a collaborative study on behalf of the 'association des Cytogénéticiens de langue Française'.	Béri-Deixheimer M	European journal of human genetics : EJHG	2007	PMID: 17290276

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NC_000020.11:g.(?_63444639)_(63528152_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...