ClinVar Genomic variation as it relates to human health

The variant chr1-1737951-C-T, GNB1(NM_002074.5):c.230G>A,p.(Gly77Asp) was identified in an individual with NDD. Inheritance was de novo (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Likely Pathogenic (criteria: PS2_Moderate, PS4_Supporting, PM2_Supporting, PM5_Moderate, PP2_Supporting, PP3_Supporting).

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

- Variant is absent from gnomAD (both v2 and v3). - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Four other missense variants have been reported in at least nine probands with neurodevelopmental delay and reported de novo where inheritance information were provided (ClinVar, DECIPHER, PMID: 27108799, 29174093, 30194818). - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least two probands, one of whom was reported to be de novo (ClinVar). - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). Additional information: - Loss of function is a known mechanism of disease in this gene and is associated with intellectual disability, autosomal dominant 42 (MIM#616973). - This gene is associated with autosomal dominant disease. - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. - This variant is heterozygous. - An alternative amino acid change at the same position has been observed in gnomAD (v3: 1 heterozygote, 0 homozygotes). - Missense variant with conflicting in silico predictions and uninformative conservation. - No published segregation evidence has been identified for this variant. - No published functional evidence has been identified for this variant.

The alteration results in an amino acid change:_x000D_ _x000D_ The c.230G>A (p.G77D) alteration is located in exon 6 (coding exon 4) of the GNB1 gene. This alteration results from a G to A substitution at nucleotide position 230, causing the glycine (G) at amino acid position 77 to be replaced by an aspartic acid (D). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GNB1 c.230G>A alteration was not observed, with coverage at this position. Alterations at the same codon has been observed in affected individuals:_x000D_ _x000D_ Several alterations have been described at the same codon to occur de novo in patients with a neurodevelopmental phenotype, including p.G77S, p.G77V, p.G77R, and p.G77A. All patients present with global developmental delay and hypotonia, while additional features have been reported in some including congenital defects, dystonia, eye abnormalities, acute lymphoblastic leukemia, and cutaneous mastocystosis (Brett, 2017; Hemati, 2018; Petrovski, 2016; Szcaluba, 2018). Additionally, de novo changes in neighboring amino acid residues (p.D76 and p.K78) have been reported in three additional individuals with global developmental delay, hypotonia, and epilepsy (Petrovski, 2016). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.G77 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.G77 amino acid is located in a WD40 repeat region in the amino-terminal interface of GNB1. Crystal structures of heterotrimeric G-alpha-beta-gamma have demonstrated that this is a region of interaction between the G-protein beta subunit and alpha subunit (Ford, 1998). The adjacent p.K78 residue is reported to play an important role in regulating activation of adenylyl cyclase 2, inhibition of calcium channels, and activation of potassium channels (Ford, 1998; Petrovski, 2016). The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.G77D alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as likely pathogenic.