VCV002424705.7 - ClinVar

NC_000023.10:g.(?_117629935)_(119761021_?)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.

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.(?_117629935)_(119761021_?)del

Variation ID: 2424705 Accession: VCV002424705.7

Type and length

Deletion, 2,131,087 bp

Location

Cytogenetic: Xq24 X: 117629935-119761021 (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 29, 2024	Apr 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NC_000023.10:g.(?_117629935)_(119761021_?)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.
CUL4B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	295	529
LAMP2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	716	888
UBE2A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	66	238
UPF3B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	263	434
NDUFA1		No evidence available	No evidence available	GRCh38 GRCh37	26	217
AKAP14		-	-	GRCh38 GRCh37	7	175
ATP1B4		-	-	GRCh38 GRCh37	30	201
C1GALT1C1		-	-	GRCh38 GRCh38 GRCh37	36	203
DOCK11		-	-	GRCh38 GRCh37	97	260
IL13RA1		-	-	GRCh38 GRCh37	20	184

There are 19 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.
X-linked intellectual disability Cabezas type	Pathogenic (1)	criteria provided, single submitter	Jul 23, 2022	RCV003113287.4
Syndromic X-linked intellectual disability 14	Pathogenic (1)	criteria provided, single submitter	Apr 21, 2023	RCV004579598.2

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 23, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	X-linked intellectual disability Cabezas type Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003791373.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (2) PubMed: 17236139‚ 25385192 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the CUL4B gene has been identified. Loss-of-function variants in CUL4B are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the CUL4B gene has been identified. Loss-of-function variants in CUL4B are known to be pathogenic (PMID: 17236139, 25385192). 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 CUL4B-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 21, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Syndromic X-linked intellectual disability 14 Affected status: unknown Allele origin: unknown	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005067289.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Publications: PubMed (2) PubMed: 17704778‚ 19238151 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with UPF3B-related conditions. … (more) For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with UPF3B-related conditions. A gross deletion of the genomic region encompassing the full coding sequence of the UPF3B gene has been identified. Loss-of-function variants in UPF3B are known to be pathogenic (PMID: 17704778, 19238151). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. (less)

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the CUL4B gene has been identified. Loss-of-function variants in CUL4B are known to be pathogenic (PMID: 17236139, 25385192). 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 CUL4B-related conditions. For these reasons, this variant has been classified as Pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with UPF3B-related conditions. A gross deletion of the genomic region encompassing the full coding sequence of the UPF3B gene has been identified. Loss-of-function variants in UPF3B are known to be pathogenic (PMID: 17704778, 19238151). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes.

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
Variants in CUL4B are associated with cerebral malformations.	Vulto-van Silfhout AT	Human mutation	2015	PMID: 25385192
Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism.	Laumonnier F	Molecular psychiatry	2010	PMID: 19238151
Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation.	Tarpey PS	Nature genetics	2007	PMID: 17704778
Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor.	Tarpey PS	American journal of human genetics	2007	PMID: 17236139

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.(?_117629935)_(119761021_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...