OPHN1

protein-coding

oligophrenin 1, the group of AH/BAR family Rho GTPase activating proteins

Gene summary

This gene encodes a Rho-GTPase-activating protein that promotes GTP hydrolysis of Rho subfamily members. Rho proteins are important mediators of intracellular signal transduction, which affects cell migration and cell morphogenesis. Mutations in this gene are responsible for OPHN1-related X-linked cognitive disability with cerebellar hypoplasia and distinctive facial dysmorhphism. [provided by RefSeq, Jul 2008]

Previous symbols:

MRX60

MANE transcript

NM_002547.3

Inheritance

ClinVar variants

P:83U:294B:108

Top phenotype

Intellectual developmental disorder, X-linked, syndromic, Billuart type

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chrX:67,949,349-68,433,913

External References & Databases

Ensembl (ENSG00000079482)

Transcript & Mutation Effects

hg38 • Region Span ~484.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked intellectual disability-cerebellar hypoplasia syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010337

Submitter: PanelApp Australia

X-linked intellectual disability-cerebellar hypoplasia syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010337

Submitter: ClinGen

*OPHN1* was first reported in relation to X-linked intellectual disability in 1998 (Billuart et al., PMID: 9582072). Affected males present with a spectrum of phenotypes including intellectual disability, cerebellar hypoplasia, and ventriculomegaly, low muscle tone (hypotonia), developmental and cognitive delay, early-onset seizures, abnormal behavior, small or underdeveloped genitals, and characteristic facial features. Carrier females may be asymptomatic or have mild learning disabilities, cognitive impairment, strabismus, and subtle dysmorphisms (PMID: 12807966). While there are reports of phenotypic variability, the variation is thought to be a single spectrum within the same disorder and therefore variants in *OPHN1* are curated under the disease entity X-linked intellectual disability and cerebellar hypoplasia syndrome. Nine variants (nonsense, missense, in-frame indel, and frameshift) that have been reported in nine probands in seven publications (PMIDs: 16221952, 16221952, 29510240, 12807966, 16158428, 25649377, 24105372) are included in this curation. Two families were included in this curation for segregation based case level evidence (PMIDs: 24105372, 29510240). Both families presented classic X-linked inheritance patterns with multiple affected males. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence. A knockout mouse model demonstrated reduced memory, reduced spatial learning, reduced dendritic spine density, and ventriculomegaly (PMID:17728457). A cellular model has also shown that *OPHN1* knockout results in decreased vesicular endocytosis at the synapses of mouse neurons (PMID:19401298). In summary, there is definitive evidence supporting the relationship between *OPHN1* and X-linked intellectual disability and cerebellar hypoplasia syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on August 24, 2023 (SOP Version 9).

X-linked intellectual disability-cerebellar hypoplasia syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010337

Submitter: G2P

X-linked intellectual disability-cerebellar hypoplasia syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010337

Submitter: Labcorp Genetics (formerly Invitae)

X-linked intellectual disability-cerebellar hypoplasia syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010337

Submitter: Orphanet

X-linked intellectual disability-cerebellar hypoplasia syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010337

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndromic, Billuart typeXL

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 9582072; 12807966; 16158428; 16221952; 20528889

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OPHN1 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 373

X-linked intellectual disability-cerebellar hypoplasia syndromeTotal: 98

Inborn genetic diseasesTotal: 78

not specifiedTotal: 40

OPHN1-related disorderTotal: 21

SeizureTotal: 2

Delayed gross motor developmentTotal: 1

Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002547.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar		18 clinvar	70 clinvar	6 clinvar	95
missense	2 clinvar	9 clinvar	240 clinvar	26 clinvar	6 clinvar	283
nonsense	12 clinvar	5 clinvar	7 clinvar			24
start loss						0
frameshift	18 clinvar	11 clinvar				29
splice donor/acceptor (+/-2bp)	11 clinvar	14 clinvar	29 clinvar			54
Total	44	39	294	96	12	485

Highest pathogenic variant AF is 0.000009101975

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002547.3	RefSeq	NP_002538.1	23	MANE Select
ENST00000355520.6	Ensembl	ENSP00000347710.5	23	MANE Select
NM_001437258.1	RefSeq	NP_001424187.1	22	Standard
ENST00000467444.1	Ensembl	ENSP00000505570.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
Rho GTPase cycle
Signaling by Rho GTPases
Regulation of RhoA activity

Biological Process

substrate-dependent cell migration, cell extension
signal transduction
nervous system development
axon guidance
cerebellar granule cell differentiation

Molecular Function

actin binding
GTPase activator activity
phospholipid binding
ionotropic glutamate receptor binding

Cellular Component

cytoplasm
cytosol
actin cytoskeleton
cell junction
terminal bouton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355520
Coding exons: 23
Length: 391570
Individuals with no LoFs: 125665
Homozygous LoFs: 1
Heterozygous LoFs: 1
Defined: 125667
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.59	174	300	0.579	0.0000222	5324
Missense (PolyPhen)		41	110.44	0.37123		1934
Synonymous	0.180	109	111	0.978	0.00000833	1485
Loss of Function	4.86	1	29.5	0.0339	0.00000201	559

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000012	0.0000088	rare
South Asian	0.000053	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Stimulates GTP hydrolysis of members of the Rho family. Its action on RHOA activity and signaling is implicated in growth and stabilization of dendritic spines, and therefore in synaptic function. Critical for the stabilization of AMPA receptors at postsynaptic sites. Critical for the regulation of synaptic vesicle endocytosis at presynaptic terminals. Required for the localization of NR1D1 to dendrites, can suppress its repressor activity and protect it from proteasomal degradation (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.197

Intolerance Scores

RVIS EVS: 0.51
RVIS percentile EVS: 80.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.759

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium