VCV002426670.4 - ClinVar

NC_000023.10:g.(?_43515590)_(44970656_?)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.

(1)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000023.10:g.(?_43515590)_(44970656_?)del

Variation ID: 2426670 Accession: VCV002426670.4

Type and length

Deletion, 1,455,067 bp

Location

Cytogenetic: Xp11.3 X: 43515590-44970656 (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	Feb 13, 2023	Jun 9, 2024	Nov 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NC_000023.10:g.(?_43515590)_(44970656_?)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.
KDM6A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	981	1179
NDP		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	18	333
MAOA		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	184	342
DUSP21		-	-	GRCh38 GRCh37	9	164
EFHC2		-	-	GRCh38 GRCh37	49	203
FUNDC1		-	-	GRCh38 GRCh37	7	165
MAOB		-	-	GRCh38 GRCh37	27	187

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.
Kabuki syndrome 2	Pathogenic (1)	criteria provided, single submitter	Nov 27, 2023	RCV003109821.5

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 (Nov 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Kabuki syndrome 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003791824.3 First in ClinVar: Feb 13, 2023 Last updated: Jun 09, 2024	Publications: PubMed (5) PubMed: 23076834‚ 23913813‚ 22197486‚ 23354975‚ 25972376 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the KDM6A gene has been identified. Loss-of-function variants in KDM6A are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the KDM6A gene has been identified. Loss-of-function variants in KDM6A are known to be pathogenic (PMID: 23076834, 23913813). 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 KDM6A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 22197486, 23354975, 25972376). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the KDM6A gene has been identified. Loss-of-function variants in KDM6A are known to be pathogenic (PMID: 23076834, 23913813). 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 KDM6A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 22197486, 23354975, 25972376). 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
Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development.	Van Laarhoven PM	Human molecular genetics	2015	PMID: 25972376
MLL2 and KDM6A mutations in patients with Kabuki syndrome.	Miyake N	American journal of medical genetics. Part A	2013	PMID: 23913813
Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate.	Lindgren AM	Human genetics	2013	PMID: 23354975
KDM6A point mutations cause Kabuki syndrome.	Miyake N	Human mutation	2013	PMID: 23076834
Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.	Lederer D	American journal of human genetics	2012	PMID: 22197486

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NC_000023.10:g.(?_43515590)_(44970656_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...