VCV001041824.7 - ClinVar

NC_000023.10:g.(?_17393881)_(20284750_?)dup

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.

(5)

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.

Uncertain significance

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.(?_17393881)_(20284750_?)dup

Variation ID: 1041824 Accession: VCV001041824.7

Type and length

Duplication, 2,890,870 bp

Location

Cytogenetic: Xp22.13-22.12 X: 17393881-20284750 (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	Mar 22, 2021	Nov 11, 2023	Aug 31, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_000023.10:g.(?_17393881)_(20284750_?)dup

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.
CDKL5		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1258	2025
NHS		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	543	729
PDHA1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	575	796
RPS6KA3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	447	632
RS1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	124	876
ADGRG2		-	-	GRCh38 GRCh37	68	251
BCLAF3	-	-	-	GRCh38 GRCh37	5	181
BEND2	-	-	-	GRCh38 GRCh37	54	228
EIF1AX		-	-	GRCh38 GRCh37	5	176
MAP3K15		-	-	GRCh38 GRCh37	132	353

There are 7 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.
Angelman syndrome-like Developmental and epileptic encephalopathy, 2	Uncertain significance (1)	criteria provided, single submitter	Aug 31, 2022	RCV001345684.3
not provided	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV003120572.6
Nance-Horan syndrome	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV003120573.6
Coffin-Lowry syndrome Intellectual disability, X-linked 19	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV003120571.6
Glycogen storage disease IXa1	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV003106199.6

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.
Uncertain significance (Aug 31, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy, 2 Angelman syndrome-like Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001539817.2 First in ClinVar: Mar 22, 2021 Last updated: Mar 26, 2023	Publications: PubMed (2) PubMed: 18076117‚ 25315662 Comment: A copy number gain of the genomic region encompassing the full coding sequence of the CDKL5 gene has been identified. The boundaries of this event … (more) A copy number gain of the genomic region encompassing the full coding sequence of the CDKL5 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. Isolated whole-gene copy number gains of CDKL5 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 18076117, 25315662). A similar copy number variant has been observed in at least one individual who was not affected with CDKL5-related conditions (Invitae). 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)
Uncertain significance (Sep 02, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV003792081 appears to (...more) Source: NCBI	Glycogen storage disease IXa1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003792081.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Comment: A copy number gain of the genomic region encompassing the full coding sequence of the PHKA2 gene has been identified. The boundaries of this event … (more) A copy number gain of the genomic region encompassing the full coding sequence of the PHKA2 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. This variant has not been reported in the literature in individuals affected with PHKA2-related conditions. 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)
Uncertain significance (Jul 12, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV003793816 appears to (...more) Source: NCBI	Coffin-Lowry syndrome Intellectual disability, X-linked 19 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003793816.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (2) PubMed: 17304053‚ 30945684 Comment: A copy number gain of the genomic region encompassing the full coding sequence of the RPS6KA3 gene has been identified. The boundaries of this event … (more) A copy number gain of the genomic region encompassing the full coding sequence of the RPS6KA3 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. Isolated whole-gene copy number gains of RPS6KA3 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 17304053, 30945684). 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)
Uncertain significance (Jul 12, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV003795678 appears to (...more) Source: NCBI	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003795678.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Comment: A gross deletion of the genomic region encompassing the full coding sequence of the SH3KBP1 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 SH3KBP1 gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SH3KBP1 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. This variant has not been reported in the literature in individuals affected with SH3KBP1-related conditions. 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)
Uncertain significance (Jul 12, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV003795278 appears to (...more) Source: NCBI	Nance-Horan syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003795278.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Comment: A copy number gain of the genomic region encompassing the full coding sequence of the NHS gene has been identified. The boundaries of this event … (more) A copy number gain of the genomic region encompassing the full coding sequence of the NHS gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. This variant has not been reported in the literature in individuals affected with NHS-related conditions. 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)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

A copy number gain of the genomic region encompassing the full coding sequence of the CDKL5 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. Isolated whole-gene copy number gains of CDKL5 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 18076117, 25315662). A similar copy number variant has been observed in at least one individual who was not affected with CDKL5-related conditions (Invitae). 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.

Comment:

A copy number gain of the genomic region encompassing the full coding sequence of the PHKA2 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. This variant has not been reported in the literature in individuals affected with PHKA2-related conditions. 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.

Comment:

A copy number gain of the genomic region encompassing the full coding sequence of the RPS6KA3 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. Isolated whole-gene copy number gains of RPS6KA3 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 17304053, 30945684). 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.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the SH3KBP1 gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SH3KBP1 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. This variant has not been reported in the literature in individuals affected with SH3KBP1-related conditions. 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.

Comment:

A copy number gain of the genomic region encompassing the full coding sequence of the NHS gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. This variant has not been reported in the literature in individuals affected with NHS-related conditions. 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
Spectrum of X-linked intellectual disabilities and psychiatric symptoms in a family harbouring a Xp22.12 microduplication encompassing the RPS6KA3 gene.	Uliana V	Journal of genetics	2019	PMID: 30945684
Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications.	Szafranski P	European journal of human genetics : EJHG	2015	PMID: 25315662
Characterization of interstitial Xp duplications in two families by tiling path array CGH.	Tzschach A	American journal of medical genetics. Part A	2008	PMID: 18076117
MLPA as first screening method for the detection of microduplications and microdeletions in patients with X-linked mental retardation.	Madrigal I	Genetics in medicine : official journal of the American College of Medical Genetics	2007	PMID: 17304053

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NC_000023.10:g.(?_17393881)_(20284750_?)dup

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...