Total submissions: 32
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 | |
Gene |
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, |
RCV000225179 | SCV001150119 | pathogenic | Intellectual disability, autosomal dominant 42 | 2019-08-19 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000418135 | SCV001250213 | pathogenic | not provided | 2018-05-01 | criteria provided, single submitter | clinical testing | |
Department of Paediatrics and Adolescent Medicine, |
RCV000225179 | SCV001364389 | pathogenic | Intellectual disability, autosomal dominant 42 | 2020-06-02 | criteria provided, single submitter | research | |
Laboratory for Molecular 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, |
RCV001255414 | SCV001431814 | pathogenic | Global developmental delay | 2019-11-01 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
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 |
Labcorp Genetics |
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, |
RCV001795309 | SCV001737591 | pathogenic | Cerebral palsy | 2021-06-10 | criteria provided, single submitter | research | |
Genomics England Pilot Project, |
RCV000225179 | SCV001759994 | likely pathogenic | Intellectual disability, autosomal dominant 42 | criteria provided, single submitter | clinical testing | ||
Génétique des Maladies du Développement, |
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, |
RCV000225179 | SCV002024864 | pathogenic | Intellectual disability, autosomal dominant 42 | 2021-04-06 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
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, |
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, |
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, |
RCV002273978 | SCV002558969 | pathogenic | Neurodevelopmental delay | criteria provided, single submitter | clinical testing | ||
Centre for Inherited Metabolic Diseases, |
RCV000225179 | SCV002757783 | pathogenic | Intellectual disability, autosomal dominant 42 | criteria provided, single submitter | clinical testing | ||
Duke University Health System Sequencing Clinic, |
RCV000225179 | SCV003918999 | pathogenic | Intellectual disability, autosomal dominant 42 | 2023-04-20 | criteria provided, single submitter | research | |
Center for Genomic Medicine, |
RCV000225179 | SCV004810050 | pathogenic | Intellectual disability, autosomal dominant 42 | 2024-04-04 | criteria provided, single submitter | clinical testing | |
Victorian Clinical Genetics Services, |
RCV000225179 | SCV005398968 | pathogenic | Intellectual disability, autosomal dominant 42 | 2024-10-09 | criteria provided, single submitter | 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 |
Laboratory of Molecular Genetics |
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, |
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, |
RCV000755055 | SCV000882871 | likely pathogenic | Seizure; Hypotonia; Neurodevelopmental Disability | 2016-05-05 | no assertion criteria provided | research | |
Clinical Genomics Laboratory, |
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, |
RCV001264641 | SCV001442856 | pathogenic | Neurodevelopmental abnormality | 2020-06-04 | no assertion criteria provided | clinical testing | |
Gene |
RCV000225179 | SCV001478316 | not provided | Intellectual disability, autosomal dominant 42 | no assertion provided | literature only | ||
Solve- |
RCV004767128 | SCV005091260 | likely pathogenic | Acute lymphoid leukemia | 2022-06-01 | no assertion criteria provided | provider interpretation | Variant confirmed as disease-causing by referring clinical team |