NM_001079872.2(CUL4B):c.95C>T (p.Pro32Leu) AND X-linked intellectual disability Cabezas type

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 2, 2024
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000190825.7

Allele description [Variation Report for NM_001079872.2(CUL4B):c.95C>T (p.Pro32Leu)]

NM_001079872.2(CUL4B):c.95C>T (p.Pro32Leu)

Genes:

LOC113845788:Sharpr-MPRA regulatory region 11856 [Gene]
CUL4B:cullin 4B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq24

Genomic location:

Preferred name:

NM_001079872.2(CUL4B):c.95C>T (p.Pro32Leu)

HGVS:

NC_000023.11:g.120560544G>A
NG_009388.1:g.20286C>T
NM_001079872.2:c.95C>TMANE SELECT
NM_001330624.2:c.110C>T
NM_003588.4:c.149C>T
NP_001073341.1:p.Pro32Leu
NP_001317553.1:p.Pro37Leu
NP_003579.3:p.Pro50Leu
NP_003579.3:p.Pro50Leu
NC_000023.10:g.119694399G>A
NM_003588.3:c.149C>T

Protein change:

P32L; PRO50LEU

Links:

OMIM: 300304.0006; dbSNP: rs869320682

NCBI 1000 Genomes Browser:

rs869320682

Molecular consequence:

NM_001079872.2:c.95C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330624.2:c.110C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003588.4:c.149C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: X-linked intellectual disability Cabezas type (MRXSC)
Synonyms:: CABEZAS SYNDROME; MENTAL RETARDATION, X-LINKED, SYNDROMIC 15; Mental retardation with short stature, hypogonadism and abnormal gait, X-linked; See all synonyms [MedGen]
Identifiers:: Gene: 114890; MONDO: MONDO:0010306; MedGen: C1845861; Orphanet: 85289; Orphanet: 85293; OMIM: 300354

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000245695	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001432395	Service de Génétique Moléculaire, Hôpital Robert Debré See additional submitters Service de Génétique Clinique, Hôpital Robert Debré	no assertion criteria provided	Likely benign (Oct 2, 2024)	unknown	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000245695

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 2015)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV001432395

Service de Génétique Moléculaire, Hôpital Robert Debré

See additional submitters

no assertion criteria provided

Likely benign
(Oct 2, 2024)

unknown

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Variants in CUL4B are associated with cerebral malformations.

Vulto-van Silfhout AT, Nakagawa T, Bahi-Buisson N, Haas SA, Hu H, Bienek M, Vissers LE, Gilissen C, Tzschach A, Busche A, Müsebeck J, Rump P, Mathijssen IB, Avela K, Somer M, Doagu F, Philips AK, Rauch A, Baumer A, Voesenek K, Poirier K, Vigneron J, et al.

Hum Mutat. 2015 Jan;36(1):106-17. doi: 10.1002/humu.22718.

PubMed [citation]

PMID:: 25385192
PMCID:: PMC4608231

Details of each submission

From OMIM, SCV000245695.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 affected brothers from a family (family 10) with the Cabezas type of X-linked syndromic intellectual developmental disorder (MRXSC; 300354), Vulto-van Silfhout et al. (2015) identified a c.149C-T transition in exon 3 of the CUL4B gene (c.149C-T, NM_003588.3), resulting in a pro50-to-leu (P50L) substitution closed to the nuclear localization signal. In vitro functional expression assays in HEK293 cells showed that the mutation resulted in caused increased levels of WDR5 (609012), one of the targets of CUL4B, suggesting impaired function of mutant CUL4B. However, the mutant protein was present at levels similar to wildtype and showed normal nuclear localization.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Service de Génétique Moléculaire, Hôpital Robert Debré, SCV001432395.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	1	not provided

Last Updated: Oct 20, 2024

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