1-1806503-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29 O:1
• Conservation: PhyloP100: 9.08

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]

ACMG classification

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 where missense usually causes diseases, GNB1
• 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/exons	MANE	UniProt
GNB1	NM_002074.5	c.239T>C	p.Ile80Thr	missense_variant	6/12	ENST00000378609.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB1	ENST00000378609.9	c.239T>C	p.Ile80Thr	missense_variant	6/12	1	NM_002074.5	P1

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

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:29 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 42 Pathogenic:14 Other:1

Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 19, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 30, 2021	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 strong, PP2 supporting -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 20, 2024	Criteria applied: PS2_VSTR,PS4,PM5_STR,PM1,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Feb 18, 2021	PS1, PS2, PS3_supporting, PM1, PM2, PP2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Program, Stanford Medicine	Sep 26, 2019	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] -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	research	Department of Paediatrics and Adolescent Medicine, The University of Hong Kong	Jun 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2023	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNB1 protein function. Experimental studies have shown that this missense change affects GNB1 function (PMID: 25485910). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -

Myelodysplastic syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2021

- -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Neurodevelopmental abnormality Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Jun 04, 2020

- -

Dystonic disorder;C0020676:Hypothyroidism;C0456070:Growth delay;C2981150:Cleft palate;C3714756:Intellectual disability;C3806604:Infantile axial hypotonia;C4021898:Upper limb hypertonia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Dec 04, 2015

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2016

- -

Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 05, 2016

- -

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

Pathogenic, no assertion criteria provided

research

Genomics And Bioinformatics Analysis Resource, Columbia University

Feb 10, 2016

- -

LEUKEMIA, CHRONIC LYMPHOCYTIC, SOMATIC Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2021

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Aug 02, 2021

de novo variant previously in Clinvar, predicted deleterious -

Cerebral palsy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Neurogenetics Research Program, University of Adelaide

Jun 10, 2021

- -

Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Nov 01, 2019

- -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 05, 2019

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;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	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

Other links and lift over

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