GNAT1
protein-codingG protein subunit alpha transducin 1, the group of G protein subunits alpha, group i
Gene summary
Transducin is a 3-subunit guanine nucleotide-binding protein (G protein) which stimulates the coupling of rhodopsin and cGMP-phoshodiesterase during visual impulses. The transducin alpha subunits in rods and cones are encoded by separate genes. This gene encodes the alpha subunit in rods. This gene is also expressed in other cells, and has been implicated in bitter taste transduction in rat taste cells. Mutations in this gene result in autosomal dominant congenital stationary night blindness. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Feb 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019118
Submitter: ClinGen
*GNAT1* was first reported in relation to autosomal recessive retinopathy in 2012 (Naeem et al, PMID: 22190596). *GNAT1 *encodes the alpha subunit of rod transducin, a heterotrimeric G protein composed of alpha, beta and gamma subunits. Transducin is an essential component of the visual transduction cascade. Specifically, the alpha subunit of transducin (T-alpha), in its inactive state, binds GDP. Upon activation by photoactivated rhodopsin, GDP is released from T-alpha and exchanged for GTP. T-alpha then dissociates from T-beta/gamma and binds the inhibitory gamma subunit of phsophodiesterase, allowing the alpha/beta subunits of PDE to hydrolyze cGMP. This results in closure of cGMP-gated channels, and hyperpolarization of the cell (PMID: 16269358). *GNAT1* associated with 2 disorders in OMIM – “Night blindness, congenital stationary, type 1G” (MIM# 616389) which is autosomal recessive; and “Night blindness, congenital stationary, autosomal dominant 3” (MIM# 610444). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in the inheritance pattern for these two conditions (as indicated by OMIM), and potentially a difference in the molecular mechanism. There is clear autosomal dominant inheritance in large pedigrees (PMID: 8673138; PMID: 17584859), while the heterozygous parents of biallelic affected individuals have appear to no signs of the condition upon detailed ophthalmological evaluation including electroretinogram (ERG) (PMID: 22190596; PMID: 26472407; PMID: 31696758) supporting autosomal recessive inheritance in these families. In addition, two missense variants that segregate in autosomal dominant pedigrees and that have been supported by functional studies, p.Gly38Asp and p.Gln200Glu, appear to result in constitutive activation of the visual transduction cascade (PMIDs: 10702259, 16793893 24009494), while the mechanism for variants identified in biallelic cases is likely to be loss of function. Therefore, these two conditions have been curated separately. Further functional studies are needed to better understand the role of different variants in *GNAT1*. Because the phenotype varies in individuals with biallelic variants in GNAT1, all cases have been lumped under “*GNAT1*-related recessive retinopathy”. While there is a possible genotype/phenotype correlation between C-terminal deletions resulting in retinal degeneration while other variants cause a more typical congenital stationary night blindness, additional evidence is needed before these conditions are split. Five variants (one missense, one in-frame deletion, one frameshift, two C-terminal nonsense variants) that have been reported in five probands in five publications (PMID: 22190596; PMID: 26472407; PMID: 27977773; PMID: 31696758; PMID: 31736247) are included in this curation. Segregation evidence was also included (PMID: 22190596). An additional case was not included due to scant clinical details and because the variants were not confirmed to be in trans PMID: 33691693) (Total genetic evidence = 6.7 points). This gene-disease relationship is also supported by experimental evidence including the important role of the gene product of *GNAT1* (the alpha-subunit of transducin) in the phototransduction cascade, which is consistent with the phenotype of individuals with damaging variants in the gene (PMID: 16269358); its interaction with the products of other genes known to be involved in retinopathy, including *RHO *(PMID: 31300275); and recapitulation of the phenotype in natural and laboratory-generated mouse models (PMID: 19766629; PMID: 11095744). Additional evidence is available in the literature but the maximum points for experimental evidence (6 points) has been reached. In summary, there is definitive evidence supporting the relationship between *GNAT1* and autosomal recessive retinopathy. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. The classification of novel variants in *GNAT1* may be challenging, given that this gene is also associated with autosomal dominant retinopathy. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on November 7, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0014614
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012497
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012497
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019118
Submitter: ClinGen
*GNAT1* was first reported in relation to autosomal dominant retinopathy in 1996 in a large family dating back to one individual, Jean Nougaret (1637-1719), a butcher who lived in Vendemian in southern France (Dryja et al, PMID: 8673138). *GNAT1* encodes the alpha subunit of rod transducin, a heterotrimeric G protein composed of alpha, beta and gamma subunits. Transducin is an essential component of the visual transduction cascade. Specifically, the alpha subunit of transducin (T-alpha), in its inactive state, binds GDP. Upon activation by photoactivated rhodopsin, GDP is released from T-alpha and exchanged for GTP. T-alpha then dissociates from T-beta/gamma and binds the inhibitory gamma subunit of phsophodiesterase, allowing the alpha/beta subunits of PDE to hydrolyze cGMP. This results in closure of cGMP-gated channels, and hyperpolarization of the cell (PMID: 16269358). *GNAT1* associated with 2 disorders in OMIM – “Night blindness, congenital stationary, type 1G” (MIM# 616389) which is autosomal recessive; and “Night blindness, congenital stationary, autosomal dominant 3” (MIM# 610444). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in the inheritance pattern for these two conditions (as indicated by OMIM), and potentially a difference in the molecular mechanism. There is clear autosomal dominant inheritance in large pedigrees (PMID: 8673138; PMID: 17584859), while the heterozygous parents of biallelic affected individuals have appear to no signs of the condition upon detailed ophthalmological evaluation including electroretinogram (ERG) (PMID: 22190596; PMID: 26472407; PMID: 31696758) supporting autosomal recessive inheritance in these families. In addition, two missense variants that segregate in autosomal dominant pedigrees and that have been supported by functional studies, p.Gly38Asp and p.Gln200Glu, appear to result in constitutive activation of the visual transduction cascade (PMIDs: 10702259, 16793893, 17584859, 24009494), while the mechanism for variants identified in biallelic cases is likely to be loss of function. Therefore, these two conditions have been curated separately. Further functional studies are needed to better understand the role of different variants in *GNAT1*. Because the phenotype varies in individuals with monoallelic variants in *GNAT1*, all cases have been lumped under “GNAT1-related dominant retinopathy”. Six variants (one missense, one in-frame deletion, one frameshift, two C-terminal nonsense variants) that have been reported in seven probands in six publications (PMID: 8673138; PMID: 17584859; PMID: 26747767; PMID: 29850563; PMID: 31583501; PMID: 34064005) are included in this curation. Segregation evidence was also included for two different variants with functional evidence that were shown to segregate with disease in families, c.113G>A (p.Gly38Asp) in the French, Nougaret family (PMID: 8673138) and c.598C>G (p.Gln200Glu) in a Danish family (PMID: 17584859) (Total genetic evidence = 5.9 points) This gene-disease relationship is also supported by experimental evidence including the important role of the gene product of *GNAT1* (the alpha-subunit of transducin) in the phototransduction cascade, which is consistent with the phenotype of individuals with damaging variants in the gene (PMID: 16269358); its interaction with the products of other genes known to be involved in retinopathy, including *RHO* (PMID: 31300275); experimental demonstrating the impact of a GNAT1 missense variant, p.Q200L (PMID: 16207703) and recapitulation of the phenotype in transgenic mice expressing the missense variant identified in the Nougaret family (PMID: 16793893) and the missense variant p.Q200L (PMID: 16207703). Additional evidence is available in the literature but the maximum points for experimental evidence (6 points) has been reached. In summary, there is definitive evidence supporting the relationship between *GNAT1* and autosomal dominant retinopathy. Specifically, two missense variants, p.Gly38Asp and p.Gln200Glu, have been shown to segregate with disease in an autosomal dominant manner and their role has been supported by functional evidence. The classification of novel variants in GNAT1 may be challenging, given that this gene is also associated with autosomal recessive retinopathy. This gene-disease relationship has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on November 7, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0004580
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014614
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012497
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GNAT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_144499.3. 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 | 6 | 88 | 1 | 95 | ||
| missense | 4 | 2 | 178 | 4 | 188 | |
| nonsense | 4 | 6 | 1 | 11 | ||
| start loss | 2 | 2 | ||||
| frameshift | 6 | 1 | 5 | 12 | ||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 14 | 14 | 192 | 92 | 1 | 313 |
Highest pathogenic variant AF is 0.00006940064
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_653082.1 | 8 | MANE Select | |
| Ensembl | ENSP00000232461.3 | 8 | MANE Select | |
| RefSeq | NP_000163.2 | 8 | Standard | |
| Ensembl | ENSP00000387555.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Phototransduction - Homo sapiens (human)
- Signaling by GPCR
- Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding
- Signal Transduction
- visual signal transduction
Biological Process
- detection of chemical stimulus involved in sensory perception of bitter taste
- protein folding
- signal transduction
- adenylate cyclase-modulating G protein-coupled receptor signaling pathway
- visual perception
Molecular Function
- acyl binding
- G protein-coupled receptor binding
- GTPase activity
- GTP binding
- GDP binding
Cellular Component
- photoreceptor outer segment
- photoreceptor inner segment
- cytosol
- heterotrimeric G-protein complex
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000232461
- Coding exons
- 8
- Length
- 4905
- Individuals with no LoFs
- 125677
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 65
- Defined
- 125742
- p
- 0.000258
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.719 | 198 | 229 | 0.866 | 0.0000157 | 2339 |
| Missense (PolyPhen) | 105 | 115.56 | 0.90865 | 1230 | ||
| Synonymous | 0.529 | 93 | 99.7 | 0.933 | 0.00000850 | 647 |
| Loss of Function | -0.177 | 18 | 17.2 | 1.05 | 8.22e-7 | 198 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00087 | 0.00087 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00021 | 0.00021 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Functions as signal transducer for the rod photoreceptor RHO. Required for normal RHO-mediated light perception by the retina (PubMed:22190596). Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs), such as the photoreceptor RHO. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Activated RHO promotes GDP release and GTP binding. Signaling is mediated via downstream effector proteins, such as cGMP-phosphodiesterase (By similarity). {ECO:0000250|UniProtKB:P04695, ECO:0000269|PubMed:22190596}.;
- Disease
- DISEASE: Night blindness, congenital stationary, autosomal dominant 3 (CSNBAD3) [MIM:610444]: A non-progressive retinal disorder characterized by impaired night vision, often associated with nystagmus and myopia. {ECO:0000269|PubMed:17584859, ECO:0000269|PubMed:8673138}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Night blindness, congenital stationary, 1G (CSNB1G) [MIM:616389]: An autosomal recessive form of congenital stationary night blindness, a non-progressive retinal disorder characterized by impaired night vision or in dim light, with good vision only on bright days. {ECO:0000269|PubMed:22190596}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.186
Intolerance Scores
- LoFtool
- 0.349
- RVIS EVS
- -0.6
- RVIS percentile EVS
- 17.75
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.633
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |