ClinVar Miner

Submissions for variant NM_002074.5(GNB1):c.233A>G (p.Lys78Arg) (rs869312823)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523590 SCV000618168 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing The K78R pathogenic variant in the GNB1 gene has been reported previously as a de novo variant in an individual with developmental delay, infantile spasms, hypotonia, and strabismus who underwent exome sequencing (Petrovski et al., 2016). The K78R variant is not observed in large population cohorts (Lek et al., 2016). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000523590 SCV001250214 pathogenic not provided 2019-06-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000225134 SCV001429205 pathogenic Mental retardation, autosomal dominant 42 2019-07-02 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed).
Ambry Genetics RCV001266591 SCV001444767 likely pathogenic Inborn genetic diseases 2018-06-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV000225134 SCV001522438 pathogenic Mental retardation, autosomal dominant 42 2019-09-27 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID: 27108799, ClinVar ID: 224714]
Institute for Genomic Medicine, Columbia University,Columbia University Medical Center RCV000210269 SCV000266335 pathogenic Global developmental delay; Seizures; Feeding difficulties; Growth delay; Strabismus; Infantile muscular hypotonia; EEG with generalized epileptiform discharges; Muscular hypotonia 2016-02-10 no assertion criteria provided research
OMIM RCV000225134 SCV000282064 pathogenic Mental retardation, autosomal dominant 42 2016-08-08 no assertion criteria provided literature only
University of Washington Center for Mendelian Genomics, University of Washington RCV000755053 SCV000882869 likely pathogenic Seizures; hypotonia; Neurodevelopmental Disability 2016-05-05 no assertion criteria provided research
GenomeConnect, ClinGen RCV001249296 SCV001423253 not provided GNB1-Related Disorder no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 09-06-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Clinical Genomics Program, Stanford Medicine RCV000225134 SCV001427087 likely pathogenic Mental retardation, autosomal dominant 42 2019-10-07 no assertion criteria provided clinical testing The p.Lys78Arg variant in the GNB1 gene has been previously reported de novo in 2 individuals with features consistent with GNB1-associated neurodevelopmental disorder (Petrovski et al., 2016; Hemati et al., 2018). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Lys78Arg 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.Lys78Arg variant as likely pathogenic for autosomal dominant GNB1-associated neurodevelopmental disorder, based on the information above. [ACMG evidence codes used: PS2_Moderate; PM1; PM2; PP2]
GeneReviews RCV000225134 SCV001478315 pathogenic Mental retardation, autosomal dominant 42 2020-02-26 no assertion criteria provided literature only

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