ClinVar Miner

Submissions for variant NM_002074.5(GNB1):c.239T>C (p.Ile80Thr) (rs752746786)

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Total submissions: 20
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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 2018-06-12 criteria provided, single submitter clinical testing The I80T variant in the GNB1 gene has been reported previously as de novo in three unrelated individuals with developmental delay and hypotonia, two of whom also had seizures (Petrovski et al., 2016). Additionally, a variant at the same residue (I80N) was identified as de novo in two individuals with developmental delay, hypotonia, and seizures, supporting the functional importance of this residue (Petrovski et al., 2016). This residue is conserved across species and has been shown to be important for inhibition of calcium channels, activation of potassium channels and a phospholipase, as well as for G-alpha binding (Petrovski et al., 2016). The I80T variant is not observed in large population cohorts (Lek et al., 2016). The I80T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret I80T as a pathogenic variant.
CeGaT Praxis fuer Humangenetik 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 Mental retardation, autosomal dominant 42 2020-06-02 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare 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 likely pathogenic Mental retardation, autosomal dominant 42 2019-01-01 criteria provided, single submitter clinical testing This variant was identified as de novo.
Invitae RCV000418135 SCV001586058 pathogenic not provided 2018-03-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 80 of the GNB1 protein (p.Ile80Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to be de novo in individuals affected with developmental delay, hypotonia and other variable features such as seizures, ophthalmological disorder, height and weight delay, and dysmorphic features (PMID: 27108799). ClinVar contains an entry for this variant (Variation ID: 208722). Experimental studies have shown that this missense change results in an activated GNB1 protein with increased cytokine-independent growth, loss of interaction with G-protein alpha subunits, and downstream signaling pathway activation (PMID: 25485910). For these reasons, this variant has been classified as Pathogenic.
Genomics England Pilot Project,Genomics England RCV000225179 SCV001759994 likely pathogenic Mental retardation, 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
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000208571 SCV000263295 pathogenic Dystonia; 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.
Institute for Genomic Medicine, Columbia University,Columbia University Medical Center RCV000210259 SCV000266337 pathogenic Global developmental delay; Expressive language delay; Seizures; Failure to thrive; Growth delay; Nystagmus; Strabismus; Developmental regression; Limb hypertonia; Inability to walk; Multifocal epileptiform discharges; EEG with generalized epileptiform discharges; Muscular hypotonia 2016-02-10 no assertion criteria provided research
OMIM RCV000225179 SCV000282059 pathogenic Mental retardation, autosomal dominant 42 2020-12-14 no assertion criteria provided literature only
OMIM RCV000225295 SCV000282060 pathogenic Myelodysplastic syndrome 2020-12-14 no assertion criteria provided literature only
OMIM RCV001007652 SCV000282061 pathogenic LEUKEMIA, CHRONIC LYMPHOCYTIC, SOMATIC 2020-12-14 no assertion criteria provided literature only
University of Washington Center for Mendelian Genomics, University of Washington RCV000755055 SCV000882871 likely pathogenic Seizures; hypotonia; Neurodevelopmental Disability 2016-05-05 no assertion criteria provided research
Institute of Human Genetics, Klinikum rechts der Isar RCV000225179 SCV001150119 pathogenic Mental retardation, autosomal dominant 42 2019-08-19 no assertion criteria provided clinical testing
Clinical Genomics Program, Stanford Medicine RCV000225179 SCV001427084 pathogenic Mental retardation, 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 pathogenic Mental retardation, autosomal dominant 42 2020-02-26 no assertion criteria provided literature only

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