1-1806503-A-G
Variant summary
Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_002074.5(GNB1):c.239T>C(p.Ile80Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I80S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002074.5 missense
Scores
Clinical Significance
Conservation
Publications
- intellectual disability, autosomal dominant 42Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P
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ACMG classification
Our verdict: Pathogenic. The variant received 15 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_002074.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GNB1 | NM_002074.5 | MANE Select | c.239T>C | p.Ile80Thr | missense | Exon 6 of 12 | NP_002065.1 | ||
| GNB1 | NM_001282539.2 | c.239T>C | p.Ile80Thr | missense | Exon 5 of 11 | NP_001269468.1 | |||
| GNB1 | NM_001282538.2 | c.-62T>C | 5_prime_UTR | Exon 4 of 10 | NP_001269467.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GNB1 | ENST00000378609.9 | TSL:1 MANE Select | c.239T>C | p.Ile80Thr | missense | Exon 6 of 12 | ENSP00000367872.3 | ||
| GNB1 | ENST00000610897.4 | TSL:5 | c.239T>C | p.Ile80Thr | missense | Exon 5 of 11 | ENSP00000481878.1 | ||
| GNB1 | ENST00000703692.1 | c.239T>C | p.Ile80Thr | missense | Exon 6 of 11 | ENSP00000515427.1 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 152188Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459226Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1AN XY: 726042 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
Age Distribution
GnomAD4 genome 0.00 AC: 0AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 42 Pathogenic:15Other:1
The p.Ile80Thr variant in the GNB1 gene has been previously reported de novo in 11 individuals with features including global developmental delay, hypotonia, seizures, and additional variable features (Hemati et al., 2018; Petrovski et al., 2016). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Ile80Thr variant is located in a mutational hotspot of GNB1; other pathogenic and likely pathogenic variants have been described at amino acid positions 76-80 and disrupt the binding of GNB1 to other subunits. The GNB1 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ile80Thr variant as pathogenic for autosomal dominant GNB1-associated neurodevelopmental disorder, based on the information above. [ACMG evidence codes used: PS2_VeryStrong; PM1; PM2; PP2]
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a suggested mechanism of disease in this gene and is associated with intellectual development disorder, 42 (MIM#616973). However, a dominant-negative disease mechanism has not been excluded for missense variants (PMID: 28087732, 32918542). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypes reported to have variability include epilepsy/seizures and brain abnormalities (PMID: 32918542). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple amino acid changes at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Ile80Asn) and p.(Ile80Ser) have been reported as pathogenic/likely pathogenic by multiple clinical laboratories (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by multiple clinical laboratories (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
The heterozygous p.Ile80Thr variant in GNB1 was identified by our study in 1 individual with intellectual disability, autosomal dominant 42. Trio exome analysis showed this variant to be de novo. This variant is assumed de novo in 1 individual, but maternity and paternity have not been confirmed (PMID: 31735425). The variant has been reported in at least 15 individuals of Japanese, North African, European non-Finnish, and unknown ethnicity with intellectual disability, autosomal dominant 42 (PMID: 25485910, 27108799, 30194818, 31735425), but was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 208722) and has been interpreted as pathogenic by many labs, and likely pathogenic by University of Washington Center for Mendelian Genomics. In vitro functional studies provide some evidence that the variant may slightly impact protein function (PMID: 25485910). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Multiple variants in the same region as p.Ile80Thr have been reported in association with disease in ClinVar and the literature and it is located in a region of GNB1 that is essential to protein folding and stability, suggesting that this variant is in a hot spot and functional domain and supports pathogenicity (PMID: 27108799). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Ile80Asn, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 27108799/Variation ID: 224715). The number of missense variants reported in GNB1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for intellectual disability, autosomal dominant 42 in an autosomal dominant manner based on reports of de novo cases, absence from control databases, multiple reports of affected individuals with the variant in the literature. ACMG/AMP Criteria applied: PS2, PM2, PS4_moderate, PS3_supporting, PM1, PM5_supporting, PP2 (Richards 2015).
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 strong, PP2 supporting
PS1, PS2, PS3_supporting, PM1, PM2, PP2
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least two similarly affected unrelated individuals (PMID: 31735425, 30194818, 27108799, PS2 and PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change ( p.Ile80Asn) at the same codon has been reported as pathogenic (PMID: 27108799, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Missense changes are a common disease-causing mechanism (PP2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Criteria applied: PS2_VSTR,PS4,PM5_STR,PM1,PM2
not provided Pathogenic:3
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27513193, 27108799, 31142838, 25485910, 30194818, 31036916, 31735425, 32963807, 34096027, 31785789)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 80 of the GNB1 protein (p.Ile80Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GNB1-related conditions (PMID: 27108799). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208722). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GNB1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GNB1 function (PMID: 25485910). For these reasons, this variant has been classified as Pathogenic.
Intellectual disability Pathogenic:2
de novo variant previously in Clinvar, predicted deleterious
Myelodysplastic syndrome Pathogenic:1
Neurodevelopmental abnormality Pathogenic:1
Neurodevelopmental delay Pathogenic:1
Dystonic disorder;C0020676:Hypothyroidism;C0456070:Growth delay;C2981150:Cleft palate;C3714756:Intellectual disability;C3806604:Infantile axial hypotonia;C4021898:Upper limb hypertonia Pathogenic:1
The same de novo variant was identified in several other patients. De novo variants were also identified in additional patients with a similar phenotype in the four codons upstream. Functional assessment of the variant was reported in PMID:25485910.
Inborn genetic diseases Pathogenic:1
Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability Pathogenic:1
Hypotonia;C0028738:Nystagmus;C0036572:Seizure;C0038379:Strabismus;C0454641:Expressive language delay;C0456070:Growth delay;C0557874:Global developmental delay;C0560046:Inability to walk;C1836830:Developmental regression;C1838391:Limb hypertonia;C2315100:Failure to thrive;C4021219:Multifocal epileptiform discharges;C4023476:EEG with generalized epileptiform discharges Pathogenic:1
LEUKEMIA, CHRONIC LYMPHOCYTIC, SOMATIC Pathogenic:1
Cerebral palsy Pathogenic:1
not specified Pathogenic:1
Global developmental delay Pathogenic:1
Acute lymphoid leukemia Pathogenic:1
Variant confirmed as disease-causing by referring clinical team
Neurodevelopmental disorder Pathogenic:1
The p.Ile80Thr variant in GNB1 has been reported in the literature as a de novo germline event in 10 individuals with clinical features of a neurodevelopmental disorder most commonly consisting of global developmental delays, hypotonia evolving to hypertonia and spasticity, abnormal vision, and epilepsy (Petrovski et al. 2016, Hemati et al. 2018) and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 208722). Additionally, another missense variant at this same codon, p.Ile80Asn, has also been reported as a de novo germline event in several unrelated individuals with neurodevelopmental features (Petrovski et al. 2016). As a somatic event, the p.Ile80Thr variant has also been identified in individuals with hematologic, primarily B-cell, malignancies (Yoda et al. 2015) and in mice transplanted with p.Ile80Thr bone marrow (Yoda et al. 2015). The implications of these findings to individuals with germline variants remains to be determined (Petrovski et al. 2016, Hemati et al. 2018). The variant occurs at a critical residue, and functional studies support that variation at amino acid 80 impacts protein function (Ford et al. 1998, Yoda et al. 2015). Lastly, computational prediction tools and conservation analysis support that the p.Ile80Thr variant impacts protein function. In summary, this variant meets criteria to be classified as pathogenic for neurodevelopmental disorder in an autosomal dominant manner based upon case counts, de novo occurrence, location at a critical residue, a different pathogenic missense at the same position, functional evidence, and predicted impact on protein. ACMG/AMP Criteria applied: PS2_VeryStrong, PM5, PM1, PS3_Supporting, PP3
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at