VCV000426723.33 - ClinVar

NM_001079872.2(CUL4B):c.953_957del (p.Ile318fs)

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.

(6)

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001079872.2(CUL4B):c.953_957del (p.Ile318fs)

Variation ID: 426723 Accession: VCV000426723.33

Type and length

Deletion, 5 bp

Location

Cytogenetic: Xq24 X: 120544607-120544611 (GRCh38) [ NCBI UCSC ] X: 119678462-119678466 (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	May 22, 2017	Dec 17, 2023	Nov 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001079872.2:c.953_957del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001073341.1:p.Ile318fs	frameshift
NM_001330624.2:c.968_972del	NP_001317553.1:p.Ile323fs	frameshift
NM_001369145.1:c.419_423del	NP_001356074.1:p.Ile140fs	frameshift
NM_003588.3:c.1007_1011delTTATA
NM_003588.4:c.1007_1011del	NP_003579.3:p.Ile336fs	frameshift
NM_003588.4:c.1007_1011delTTATA
NC_000023.11:g.120544610_120544614del
NC_000023.10:g.119678465_119678469del
NG_009388.1:g.36219_36223del

... more HGVS ... less HGVS

Protein change

I318fs, I323fs, I336fs, I140fs

Other names

Canonical SPDI

NC_000023.11:120544606:TATAATAT:TAT

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

ClinGen: CA645294134 dbSNP: rs1085307760 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

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 6, 2017	RCV000489216.4
X-linked intellectual disability Cabezas type	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Nov 20, 2023	RCV000590902.7

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 (Apr 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability Cabezas type Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000700148.1 First in ClinVar: Mar 23, 2018 Last updated: Mar 23, 2018	Sex: male
Pathogenic (Apr 06, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577249.3 First in ClinVar: May 22, 2017 Last updated: May 22, 2017	Comment: The c.1007_1011delTTATA variant in the CUL4B gene has been reported previously in families with X-linked intellectual disability (Tarpey et al., 2007; Vulto-van Silfhout et al., … (more) The c.1007_1011delTTATA variant in the CUL4B gene has been reported previously in families with X-linked intellectual disability (Tarpey et al., 2007; Vulto-van Silfhout et al., 2015). The c.1007_1011delTTATA variant causes a frameshift starting with codon Isoleucine 336, changes this amino acid to a Lysine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Ile336LysfsX2. Functional studies on patient-derived cells demonstrate that this variant significantly reduces CUL4B gene expression (Kerzendorfer et al., 2010). The c.1007_1011delTTATA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1007_1011delTTATA as a pathogenic variant. (less)
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability Cabezas type Affected status: yes Allele origin: germline	3billion Accession: SCV002573184.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 17236139 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000426723 / PMID: 17236139). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Intellectual disability (present) , Toe syndactyly (present) , Gowers sign (present) , Cryptorchidism (present) , Retrognathia (present)
Pathogenic (Nov 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability Cabezas type Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004176009.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: Criteria applied: PVS1,PS2,PS4_MOD,PM2_SUP Clinical Features: Epicanthus (present) , Short stature (present) , Abnormal circulating enzyme concentration or activity (present) , Moderate global developmental delay (present) , Hypotelorism (present) , Prominent … (more) Epicanthus (present) , Short stature (present) , Abnormal circulating enzyme concentration or activity (present) , Moderate global developmental delay (present) , Hypotelorism (present) , Prominent forehead (present) , Ischemic stroke (present) , Microcephaly (present) , Fetal growth restriction (present) (less) Sex: male
Pathogenic (May 13, 2021)	no assertion criteria provided Method: clinical testing	X-linked intellectual disability Cabezas type Affected status: yes Allele origin: de novo	Pediatric Genetics Clinic, Sheba Medical Center Accession: SCV001712168.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Clinical Features: Global developmental delay (present) , Seizure (present) , Apraxia (present) , Congenital laryngomalacia (present) , Subglottic stenosis (present) , Recurrent hand flapping (present) , Happy … (more) Global developmental delay (present) , Seizure (present) , Apraxia (present) , Congenital laryngomalacia (present) , Subglottic stenosis (present) , Recurrent hand flapping (present) , Happy demeanor (present) , Smooth philtrum (present) , Microtia (present) (less) Secondary finding: no
Pathogenic (-)	no assertion criteria provided Method: clinical testing	X-linked intellectual disability Cabezas type Affected status: unknown Allele origin: maternal	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University Accession: SCV003840184.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023

Comment:

The c.1007_1011delTTATA variant in the CUL4B gene has been reported previously in families with X-linked intellectual disability (Tarpey et al., 2007; Vulto-van Silfhout et al., 2015). The c.1007_1011delTTATA variant causes a frameshift starting with codon Isoleucine 336, changes this amino acid to a Lysine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Ile336LysfsX2. Functional studies on patient-derived cells demonstrate that this variant significantly reduces CUL4B gene expression (Kerzendorfer et al., 2010). The c.1007_1011delTTATA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1007_1011delTTATA as a pathogenic variant.

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000426723 / PMID: 17236139). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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
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 rs1085307760 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_001079872.2(CUL4B):c.953_957del (p.Ile318fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1085307760 ...