Submissions for variant NM_002074.5(GNB1):c.239T>C (p.Ile80Thr)

dbSNP: rs752746786

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190738	SCV000244179	pathogenic	Inborn genetic diseases	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000418135	SCV000529467	pathogenic	not provided	2021-11-19	criteria provided, single submitter	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)
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000225179	SCV001150119	pathogenic	Intellectual disability, autosomal dominant 42	2019-08-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000418135	SCV001250213	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong	RCV000225179	SCV001364389	pathogenic	Intellectual disability, autosomal dominant 42	2020-06-02	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195548	SCV001365933	pathogenic	Neurodevelopmental disorder	2019-06-05	criteria provided, single submitter	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
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001255414	SCV001431814	pathogenic	Global developmental delay	2019-11-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000225179	SCV001440423	pathogenic	Intellectual disability, autosomal dominant 42	2024-02-20	criteria provided, single submitter	clinical testing	Criteria applied: PS2_VSTR,PS4,PM5_STR,PM1,PM2_SUP
Invitae	RCV000418135	SCV001586058	pathogenic	not provided	2023-08-10	criteria provided, single submitter	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). 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.
Neurogenetics Research Program, University of Adelaide	RCV001795309	SCV001737591	pathogenic	Cerebral palsy	2021-06-10	criteria provided, single submitter	research
Genomics England Pilot Project, Genomics England	RCV000225179	SCV001759994	likely pathogenic	Intellectual disability, autosomal dominant 42		criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001544504	SCV001762519	pathogenic	Intellectual disability	2021-08-02	criteria provided, single submitter	clinical testing	de novo variant previously in Clinvar, predicted deleterious
3billion	RCV000225179	SCV002011971	pathogenic	Intellectual disability, autosomal dominant 42	2021-10-02	criteria provided, single submitter	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.
Revvity Omics, Revvity	RCV000225179	SCV002024864	pathogenic	Intellectual disability, autosomal dominant 42	2021-04-06	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000225179	SCV002102990	pathogenic	Intellectual disability, autosomal dominant 42	2021-02-18	criteria provided, single submitter	clinical testing	PS1, PS2, PS3_supporting, PM1, PM2, PP2
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000225179	SCV002507036	pathogenic	Intellectual disability, autosomal dominant 42	2022-05-04	criteria provided, single submitter	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).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000225179	SCV002512384	pathogenic	Intellectual disability, autosomal dominant 42	2021-11-30	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 strong, PP2 supporting
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273978	SCV002558969	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000225179	SCV002757783	pathogenic	Intellectual disability, autosomal dominant 42		criteria provided, single submitter	clinical testing
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000225179	SCV003918999	pathogenic	Intellectual disability, autosomal dominant 42	2023-04-20	criteria provided, single submitter	research
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000208571	SCV000263295	pathogenic	Dystonic disorder; Growth delay; Hypothyroidism; Intellectual disability; Infantile axial hypotonia; Upper limb hypertonia; Cleft palate	2015-12-04	no assertion criteria provided	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.
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000210259	SCV000266337	pathogenic	Global developmental delay; Expressive language delay; Seizure; Failure to thrive; Growth delay; Nystagmus; Strabismus; Developmental regression; Limb hypertonia; Inability to walk; Multifocal epileptiform discharges; EEG with generalized epileptiform discharges; Hypotonia	2016-02-10	no assertion criteria provided	research
OMIM	RCV000225179	SCV000282059	pathogenic	Intellectual disability, autosomal dominant 42	2021-11-02	no assertion criteria provided	literature only
OMIM	RCV000225295	SCV000282060	pathogenic	Myelodysplastic syndrome	2021-11-02	no assertion criteria provided	literature only
OMIM	RCV001007652	SCV000282061	pathogenic	LEUKEMIA, CHRONIC LYMPHOCYTIC, SOMATIC	2021-11-02	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755055	SCV000882871	likely pathogenic	Seizure; Hypotonia; Neurodevelopmental Disability	2016-05-05	no assertion criteria provided	research
Clinical Genomics Program, Stanford Medicine	RCV000225179	SCV001427084	pathogenic	Intellectual disability, autosomal dominant 42	2019-09-26	no assertion criteria provided	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]
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001264641	SCV001442856	pathogenic	Neurodevelopmental abnormality	2020-06-04	no assertion criteria provided	clinical testing
GeneReviews	RCV000225179	SCV001478316	not provided	Intellectual disability, autosomal dominant 42		no assertion provided	literature only