VCV000831360.40 - ClinVar

NC_000009.11:g.(?_138645763)_(140729425_?)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_000009.11:g.(?_138645763)_(140729425_?)del

Variation ID: 831360 Accession: VCV000831360.40

Type and length

Deletion, 2,083,663 bp

Location

Cytogenetic: 9q34.3 9: 138645763-140729425 (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	Apr 15, 2020	Jun 9, 2024	May 10, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NC_000009.11:g.(?_138645763)_(140729425_?)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.
EHMT1		Sufficient evidence for dosage pathogenicity	Little evidence for dosage pathogenicity	GRCh38 GRCh37	2084	2394
NOTCH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3494	3765
ABCA2		-	-	GRCh38 GRCh37	358	481
AGPAT2		-	-	GRCh38 GRCh37	197	278
AJM1	-	-	-	GRCh38 GRCh37	-	83
ANAPC2		-	-	GRCh38 GRCh37	38	138
ARRDC1		-	-	GRCh38 GRCh37	45	205
C8G		-	-	GRCh38 GRCh37	32	119
C9orf163	-	-	-	GRCh38 GRCh37	-	92
CAMSAP1		-	-	GRCh38 GRCh37	123	197

There are 69 more genes affected by this variant. See the full set of genes in Variation Viewer (GRCh37) and ClinGen Dosage Sensitivity Map.

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.
Kleefstra syndrome 1	Pathogenic (1)	criteria provided, single submitter	May 10, 2019	RCV001031921.9
Autosomal dominant nocturnal frontal lobe epilepsy 5 Developmental and epileptic encephalopathy, 14	Uncertain significance (1)	criteria provided, single submitter	May 7, 2019	RCV001362982.14

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 (May 10, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Kleefstra syndrome 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001195228.1 First in ClinVar: Apr 15, 2020 Last updated: Apr 15, 2020	Publications: PubMed (2) PubMed: 27891178‚ 19264732 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the EHMT1 gene has been identified. The boundaries of this event are … (more) A gross deletion of the genomic region encompassing the full coding sequence of the EHMT1 gene has been identified. The boundaries of this event are unknown as the deletion extends beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of EHMT1 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 19264732, 27891178). Loss-of-function variants in EHMT1 are known to be pathogenic (PMID: 16826528, 19264732). For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (May 07, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal dominant nocturnal frontal lobe epilepsy 5 Developmental and epileptic encephalopathy, 14 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: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001559050.5 First in ClinVar: Apr 13, 2021 Last updated: Jun 09, 2024	Comment: 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 … (more) 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. This variant has not been reported in the literature in individuals with KCNT1-related conditions. This variant is a gross deletion of the genomic region encompassing exons 5-31 of the KCNT1 gene. The 5' boundary is likely confined to intron 4. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. (less)

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the EHMT1 gene has been identified. The boundaries of this event are unknown as the deletion extends beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of EHMT1 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 19264732, 27891178). Loss-of-function variants in EHMT1 are known to be pathogenic (PMID: 16826528, 19264732). For these reasons, this variant has been classified as Pathogenic.

Comment:

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. This variant has not been reported in the literature in individuals with KCNT1-related conditions. This variant is a gross deletion of the genomic region encompassing exons 5-31 of the KCNT1 gene. The 5' boundary is likely confined to intron 4. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation.

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
Enrichment of small pathogenic deletions at chromosome 9p24.3 and 9q34.3 involving DOCK8, KANK1, EHMT1 genes identified by using high-resolution oligonucleotide-single nucleotide polymorphism array analysis.	Wang JC	Molecular cytogenetics	2016	PMID: 27891178
Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.	Kleefstra T	Journal of medical genetics	2009	PMID: 19264732

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NC_000009.11:g.(?_138645763)_(140729425_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...