GNB1

protein-coding

G protein subunit beta 1, the group of G protein subunits beta|WD repeat domain containing

Gene summary

Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

MANE transcript

NM_002074.5

Inheritance

ClinVar variants

P:72U:112B:128

Top phenotype

Intellectual development disorder, autosomal dominant 42

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:1,785,285-1,892,292

External References & Databases

Ensembl (ENSG00000078369)

Transcript & Mutation Effects

hg38 • Region Span ~107.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 42DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014855

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 42STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014855

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 42DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014855

Submitter: Illumina

intellectual developmental disorder, autosomal dominant 42MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014855

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 42DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014855

Submitter: ClinGen

*GNB1* was first reported in relation to autosomal dominant *GNB1*-related neurodevelopmental disorder (also known as autosomal dominant intellectual disability 42 or GNB1 encephalopathy) in 2016 (Petrovski et al., PMID: 27108799). *GNB1* encodes a β subunit of the heterotrimeric G protein complex, which functions as a signal transducer for G-protein coupled receptors and is involved in numerous signaling pathways (PMID: 18488142). The disorder is characterized by global developmental delay, moderate-to-severe intellectual disability, delayed or absent speech, hypotonia, seizures, abnormal vision, and structural brain abnormalities. Other less common findings include dystonia, behavior problems, growth delay, craniofacial defects, and genitourinary abnormalities in males. Twenty-five unique missense variants that have been reported in 31 probands in 6 publications (PMIDs: 27108799, 27668284, 27759915, 28087732, 29174093, 30194818) are included in this curation. More evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. The majority of reported missense variants are found in exons 6 and 7 of the *GNB1* gene, in regions critical for protein interaction, and occur *de novo* (PMID: 18488142). The most common variant reported to date, p.Ile80Thr, has been identified in at least 13 individuals (PMIDs: 27108799, 30194818, 31735425, 37453880). The mechanism of pathogenicity is currently unclear but functional analyses of multiple missense variants supports loss of function of the G-protein complex via deficits in dimer formation, heterotrimer assembly, or receptor-driven activation (PMIDs: 28087732, 34522861, 37275776). Variants may have additional loss- or gain-of-function effects on downstream signaling, as demonstrated by the K78R and I80T/N variants, which show gain-of-function (K78R) and loss-of-function (I80T/N) effects on G protein-coupled potassium (GIRK) channel activation (PMIDs: 34522861, 37275776). At least 7 truncating variants (frameshift, splice site and nonsense) have been reported to date in individuals with neurodevelopmental disorders (PMIDs: 28087732, 32345733, 32918542). *GNB1* is highly intolerant to loss-of-function variation (pLI = 1, gnomAD v2.1.1) and to missense variation (Z score = 3.83). However, it is currently unclear whether haploinsufficiency is a mechanism of disease and therefore, these variants were not included in this curation. Additional evidence is needed to clarify the implication of truncating variants in this disorder. This gene-disease relationship is also supported by a mouse model of the K78R variant which showed developmental delay, spatial learning and memory deficits, seizures and abnormal neuronal excitability (PMIDs: 36405774, 37275776). Of note, *Gnb1* haploinsufficient mice did not display enhanced seizure susceptibility (PMID: 37275776). In summary, there is definitive evidence supporting the relationship between *GNB1* and autosomal dominant *GNB1*-related neurodevelopmental disorder. 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 ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 16, 2023 (SOP Version 9).

intellectual developmental disorder, autosomal dominant 42DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014855

Submitter: G2P

intellectual developmental disorder, autosomal dominant 42STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014855

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual development disorder, autosomal dominant 42AD

Manifestation: Craniofacial; Neurologic; Ophthalmologic

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: 27108799

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNB1 variants in ClinVar

42 Conditions Cataloged

not providedTotal: 333

Intellectual disability, autosomal dominant 42Total: 67

not specifiedTotal: 31

Inborn genetic diseasesTotal: 27

GNB1-related disorderTotal: 20

Intellectual disabilityTotal: 11

HypotoniaTotal: 9

SeizureTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002074.5. 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			2 clinvar	106 clinvar	1 clinvar	109
missense	15 clinvar	39 clinvar	104 clinvar	14 clinvar	7 clinvar	179
nonsense	4 clinvar		1 clinvar			5
start loss						0
frameshift	5 clinvar	2 clinvar	2 clinvar			9
splice donor/acceptor (+/-2bp)	4 clinvar	3 clinvar	3 clinvar			10
Total	28	44	112	120	8	312

Highest pathogenic variant AF is 0.0000055032215

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 267 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002074.5	RefSeq	NP_002065.1	9	MANE Select
ENST00000378609.9	Ensembl	ENSP00000367872.3	9	MANE Select
NM_001282538.2	RefSeq	NP_001269467.1	5	Standard
NM_001282539.2	RefSeq	NP_001269468.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gnb1a	Danio rerio	Structure: neuromast Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

gnb1a

Danio rerio

Structure: neuromast

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Relaxin signaling pathway - Homo sapiens (human)
Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
Retrograde endocannabinoid signaling - Homo sapiens (human)
GABAergic synapse - Homo sapiens (human)

Biological Process

protein folding
signal transduction
G protein-coupled receptor signaling pathway
adenylate cyclase-activating dopamine receptor signaling pathway
phospholipase C-activating G protein-coupled receptor signaling pathway

Molecular Function

GTPase activity
protein binding
spectrin binding
protein-containing complex binding
alkylglycerophosphoethanolamine phosphodiesterase activity

Cellular Component

photoreceptor inner segment
lysosomal membrane
cytosol
heterotrimeric G-protein complex
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378609
Coding exons: 9
Length: 105767
Individuals with no LoFs: 125083
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125084
p: 0.00000400

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.83	64	226	0.283	0.0000145	2239
Missense (PolyPhen)		11	77.385	0.14215		821
Synonymous	0.328	86	90.0	0.956	0.00000623	667
Loss of Function	4.21	0	20.6	0.00	0.00000122	190

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	0.0	absent
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein- effector interaction.;
Disease: DISEASE: Mental retardation, autosomal dominant 42 (MRD42) [MIM:616973]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD42 patients manifest global developmental delay commonly accompanied by hypotonia, seizures of various types, ophthalmological manifestations, and poor growth. {ECO:0000269|PubMed:25485910, ECO:0000269|PubMed:27108799, ECO:0000269|PubMed:27668284, ECO:0000269|PubMed:28087732}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.260

Intolerance Scores

RVIS EVS: -0.32
RVIS percentile EVS: 31.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.873

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Low	Low	Low
Cancer	Low	Low	Low