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

dbSNP: rs869312823

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523590	SCV000618168	pathogenic	not provided	2023-02-27	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27108799, 30194818, 35253369, 32918542, 34522861, 36405774, 34646230)
CeGaT Center for Human Genetics 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	Intellectual disability, 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	Intellectual disability, 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]
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV002287394	SCV002577720	pathogenic	Global developmental delay-neuro-ophthalmological abnormalities-seizures-intellectual disability syndrome	2022-10-04	criteria provided, single submitter	clinical testing	PS4;PM1;PM2_supporting;PM6;PP2;PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000523590	SCV003522733	likely pathogenic	not provided	2023-07-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 224714). This missense change has been observed in individual(s) with GNB1-related conditions (PMID: 27108799, 30194818). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 78 of the GNB1 protein (p.Lys78Arg). 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 not expected to disrupt GNB1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
3billion	RCV000225134	SCV004013517	pathogenic	Intellectual disability, autosomal dominant 42		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000224714 / PMID: 27108799). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27108799). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Illumina Laboratory Services, Illumina	RCV000225134	SCV004014726	pathogenic	Intellectual disability, autosomal dominant 42	2023-03-20	criteria provided, single submitter	clinical testing	The GNB1 c.233A>G (p.Lys78Arg) missense variant results in the substitution of lysine at amino acid position 78 with arginine. This variant has been reported in a heterozygous state in three individuals with a neurodevelopmental phenotype (PMID: 27108799; PMID: 30194818; PMID: 35253369). In all three individuals the variant was reported to have occurred in a de novo state. The c.233A>G variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. A heterozygous knock-in Gnb1 K78R mouse model recapitulates features of disease observed in patients including a reduced growth rate, developmental delay, motor and cognitive deficits, and absence-like generalized seizures (PMID: 36405774; https://doi.org/10.1101/697235). The c.233A>G variant lies within an established mutational hotspot within exon 6 which encodes a region at the G-beta subunit1 surface which interacts with G-alpha subunits and downstream effectors (PMID: 30194818). This variant was identified in a de novo state. Based on the available evidence, the c.233A>G (p.Lys78Arg) variant is classified as pathogenic for intellectual developmental disorder.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000225134	SCV005043970	pathogenic	Intellectual disability, autosomal dominant 42	2024-03-28	criteria provided, single submitter	clinical testing	PS2_Very Strong, PS4, PM1, PM2, PM6, PP2
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000210269	SCV000266335	pathogenic	Global developmental delay; Seizure; Feeding difficulties; Growth delay; Strabismus; Infantile muscular hypotonia; EEG with generalized epileptiform discharges; Hypotonia	2016-02-10	no assertion criteria provided	research
OMIM	RCV000225134	SCV000282064	pathogenic	Intellectual disability, autosomal dominant 42	2021-11-02	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755053	SCV000882869	likely pathogenic	Seizure; 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 Laboratory, Stanford Medicine	RCV000225134	SCV001427087	likely pathogenic	Intellectual disability, 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	not provided	Intellectual disability, autosomal dominant 42		no assertion provided	literature only