ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
28087732 Lohmann et al. (2017) performed trio exome sequencing in sixteen pediatric patients and identified 14 novel variants [2 splice site - de novo; 2 frameshift - de novo; and 10 missense mutations - 9 de novo and 1 mutation (p.P96L) with dominant inheritance in three different ethnic families]. These patients presented with common features such as global developmental delay, intellectual disability, seizures, nystagmus, muscular hypotonia and ophthalmoplegia. The guanine nucleotide-binding protein, beta 1 (GNB1) gene encodes the G-beta1 subunit of the heterotrimeric G proteins, which is a transducer of signals from G protein-coupled receptors. The two splice sites (c.268-1G>T and c.917-1G>T) and frameshift (c.272_275del and c.915_916del) mutations were predicted to have loss-of-function. Meanwhile, functional studies were conducted to understand the ability of the G-beta1 mutant protein (due to missense mutation) to interact with G-gamma and G-alpha subunits, and that the G-alpha-beta-gamma complex can still couple with dopamine D1R receptors. The interactions were assessed by real-time live-cell bioluminescence resonance energy transfer (BRET) assays. The results showed altered functionality for p.R52G, p.G64V, p.A92T, p.P94S, p.P96L, p.A106T and p.D118G missense mutations, which demonstrated their pathogenicity and considered as disease-causing. However, the p.L30F, p.H91R and p.K337Q missense mutations were found to have normal function in this experiment.

Haploinsufficiency phenotype comments:

Szczaluba et al. (2018) reported a female with intellectual disability, developmental delay, hypotonia, dysmorphism, extrapyramidal features, vesicoureteral reflux, hypothyroidism and cutaneous mastocytosis. Whole exome sequencing found a de novo missense mutation in exon 6 (c.230G>T, p.Gly77Val), which was not observed in an in-house 500 exomes as well as ExAC, 1000Genomes and ESP6500 databases. In-silico prediction software had suggested a damaging effect for this mutation. PMID: 29174093. Steinrucke et al. (2016) reported a 15 year old girl with motor and cognitive milestone delayed, non-ambulatory, speech impairment, hypotonia and generalised dystonia. Exome sequencing identified a de novo missense mutation of GNB1 gene (c.353A>G, p.D118G) at exon 7, which was not observed in 186 controls and ExAC databases. The combined annotation dependent depletion (CADD) score was 31, predicting damaging/pathogenic effect. PMID: 27668284. Notably, ClinVar Variants database had thirteen likely pathogenic/pathogenic and three uncertain significance missense mutations, but no benign missense mutation reported (Last reviewed Oct 2017). Other information: Hemati et al. (2018) (PMID: 30194818) described eighteen patients with de novo mutation of the GNB1 gene identified through trio whole exome sequencing. The common clinical features included moderate to severe developmental delay, non-ambulatory, nonverbal, hypotonia, dystonia, growth delay, gastrointestinal anomalies, increased risk of mastocytosis and half of male patients had genitourinary abnormalities. The most observed mutation was p.Ile80Thr (seen in eight patients), which was located in exon 6. Other reported missense variants were p.Leu95Pro (in two patients), p.Asp118Gly (in two patients), p.Lys78Arg, p.Cys114Tyr, p.Ala92Asp, p.Lys89Arg, p.Gly53Glu and p.Gly77Arg. Patient 3 had the p.Cys114Tyr variant in 18% allelic fraction suggesting somatic mosaicism, which explained the milder phenotype. Majority of the variants reside in exons 6 and 7. Petrovski et al. (2016) reported thirteen individuals amongst 5,855 patients with a de novo missense mutation of GNB1 gene identified by whole exome sequencing. The shared clinical features included global developmental delay, hypotonia, seizures, growth delay, multifocal epileptiform discharges, expressive language delay, vision abnormalities, inability to walk and nystagmus. The nine missense mutations found in the affected individuals were p.Asp76Gly, p.Asp76Glu, p.Gly77Ser, p.Lys78Arg, p.Ile80Asn, p.Ile80Thr, p.Leu95Pro, p.Met101Val and p.Ala326Thr. The combined annotation dependent depletion (CADD) score predicted these missense mutations to be among the 1% most deleterious substitutions in the human genome. (PMID: 27108799).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity