chr1-1806503-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_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. I80N) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

GNB1
NM_002074.5 missense

Scores

10
5
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31O:1

Conservation

PhyloP100: 9.08
Variant links:
Genes affected
GNB1 (HGNC:4396): (G protein subunit beta 1) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_002074.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-1806503-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 224715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the GNB1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 3.8328 (above the threshold of 3.09). Trascript score misZ: 3.4817 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 42.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.828
PP5
Variant 1-1806503-A-G is Pathogenic according to our data. Variant chr1-1806503-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1806503-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNB1NM_002074.5 linkc.239T>C p.Ile80Thr missense_variant Exon 6 of 12 ENST00000378609.9 NP_002065.1 P62873-1A0A140VJJ8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNB1ENST00000378609.9 linkc.239T>C p.Ile80Thr missense_variant Exon 6 of 12 1 NM_002074.5 ENSP00000367872.3 P62873-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152188
Hom.:
0
Cov.:
32
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459226
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
726042
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74354
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:31Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 42 Pathogenic:15Other:1
Nov 02, 2021
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Aug 19, 2019
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 04, 2022
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

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). -

-
Genomics England Pilot Project, Genomics England
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Feb 18, 2021
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS1, PS2, PS3_supporting, PM1, PM2, PP2 -

Nov 30, 2021
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 strong, PP2 supporting -

Apr 20, 2023
Duke University Health System Sequencing Clinic, Duke University Health System
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

-
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 09, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 -

Oct 02, 2021
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 26, 2019
Clinical Genomics Laboratory, Stanford Medicine
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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] -

Mar 04, 2025
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PS2_VSTR,PS4,PM5_STR,PM1,PM2 -

Apr 06, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 04, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 02, 2020
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

not provided Pathogenic:3
Dec 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 01, 2018
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 19, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Myelodysplastic syndrome Pathogenic:1
Nov 02, 2021
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Neurodevelopmental delay Pathogenic:1
-
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Neurodevelopmental abnormality Pathogenic:1
Jun 04, 2020
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dystonic disorder;C0020676:Hypothyroidism;C0456070:Growth delay;C2981150:Cleft palate;C3714756:Intellectual disability;C3806604:Infantile axial hypotonia;C4021898:Upper limb hypertonia Pathogenic:1
Dec 04, 2015
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

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
Apr 21, 2016
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability Pathogenic:1
May 05, 2016
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

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
Feb 10, 2016
Genomics And Bioinformatics Analysis Resource, Columbia University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

LEUKEMIA, CHRONIC LYMPHOCYTIC, SOMATIC Pathogenic:1
Nov 02, 2021
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Intellectual disability Pathogenic:1
Aug 02, 2021
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

de novo variant previously in Clinvar, predicted deleterious -

Cerebral palsy Pathogenic:1
Jun 10, 2021
Neurogenetics Research Program, University of Adelaide
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Global developmental delay Pathogenic:1
Nov 01, 2019
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Acute lymphoid leukemia Pathogenic:1
Jun 01, 2022
Solve-RD Consortium
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Neurodevelopmental disorder Pathogenic:1
Jun 05, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
28
DANN
Benign
0.97
DEOGEN2
Uncertain
0.43
T;T;T;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;.;D;D;D
M_CAP
Benign
0.036
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D
MetaSVM
Benign
-0.41
T
MutationAssessor
Uncertain
2.3
M;M;.;.;.
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-4.1
.;D;D;D;D
REVEL
Uncertain
0.52
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Uncertain
0.025
D;D;.;.;.
Polyphen
0.99
D;D;.;.;.
Vest4
0.96
MutPred
0.52
Loss of stability (P = 0.0086);Loss of stability (P = 0.0086);.;Loss of stability (P = 0.0086);Loss of stability (P = 0.0086);
MVP
0.93
MPC
3.4
ClinPred
1.0
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752746786; hg19: chr1-1737942; COSMIC: COSV66099796; API