ClinVar Miner

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

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Total submissions: 7
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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 Lines of evidence used in support of classification: SUSPECTED CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected
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.
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
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.
OMIM RCV000225179 SCV000282059 pathogenic Mental retardation, autosomal dominant 42 2016-08-08 no assertion criteria provided literature only
OMIM RCV000225295 SCV000282060 pathogenic Myelodysplastic syndrome 2016-08-08 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

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