GNB5

Chr 15AR

G protein subunit beta 5

Also known as: GB5, HG2E, IDDCA, LADCI, LDMLS1, LDMLS2, gbeta5

NCBI Gene: 10681ENSG00000069966UniProt: O14775

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. Alternatively spliced transcript variants encoding different isoforms exist. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmiaMIM #617173
AR
Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmiaMIM #617182
AR
239
ClinVar variants
53
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GNB5
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
53 Pathogenic / Likely Pathogenic· 92 VUS of 239 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.97LOEUF
pLI 0.000
Z-score 1.66
OE 0.63 (0.42–0.97)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.50Z-score
OE missense 0.72 (0.64–0.82)
167 obs / 231.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.63 (0.42–0.97)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.64–0.82)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 15 / 23.7Missense obs/exp: 167 / 231.4Syn Z: 0.13

ClinVar Variant Classifications

239 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic17
VUS92
Likely Benign43
Benign51
36
Pathogenic
17
Likely Pathogenic
92
VUS
43
Likely Benign
51
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
3
22
1
36
Likely Pathogenic
7
2
8
0
17
VUS
3
80
9
0
92
Likely Benign
1
1
30
11
43
Benign
0
1
45
5
51
Total218711417239

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GNB5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GNB5-related sinus bradycardia and cognitive disability

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmia

MIM #617173

Molecular basis of disorder known

Autosomal recessive

Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmia

MIM #617182

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — GNB5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The epileptology of GNB5 encephalopathy.
Poke G et al.·Epilepsia
2019Case report
[Intellectual developmental disorder with cardiac arrhythmia syndrome in a family caused by GNB5 variation and literature review].
Mai JH et al.·Zhonghua Er Ke Za Zhi
2020Review
Gene mutations in comorbidity of epilepsy and arrhythmia.
Yu C et al.·J Neurol
2023Review
GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.
Lodder EM et al.·Am J Hum Genet
2016
SUDEP risk and autonomic dysfunction in genetic epilepsies.
Sahly AN et al.·Auton Neurosci
2022Review
Generation of the induced human pluripotent stem cell lines CSSi009-A from a patient with a GNB5 pathogenic variant, and CSSi010-A from a CRISPR/Cas9 engineered GNB5 knock-out human cell line.
Malerba N et al.·Stem Cell Res
2019
DNA methylation biomarkers for cervical cancer risk prediction in HIV-positive Nigerian women.
Zheng Y et al.·Int J Cancer
2025
Extended Phenotyping and Functional Validation Facilitate Diagnosis of a Complex Patient Harboring Genetic Variants in MCCC1 and GNB5 Causing Overlapping Phenotypes.
Shao Z et al.·Genes (Basel)
2021Case report
Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome.
De Nittis P et al.·J Med Genet
2021
ITGB4/GNB5 axis promotes M2 macrophage reprogramming in NSCLC metastasis.
Huang X et al.·Int Immunopharmacol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools