Submission Details

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).