rs869312823

Positions:

• chr1-1806509-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_002074.5(GNB1):​c.233A>G​(p.Lys78Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:2
• Conservation: PhyloP100: 7.82

Genes affected

GNB1 (HGNC:4396): (G protein subunit beta 1) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

GNB1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a strand (size 5) in uniprot entity GBB1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_002074.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNB1. . Gene score misZ 3.8328 (greater than the threshold 3.09). Trascript score misZ 3.4817 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 42.
• PP5: Variant 1-1806509-T-C is Pathogenic according to our data. Variant chr1-1806509-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1806509-T-C is described in Lovd as [Likely_pathogenic]. Variant chr1-1806509-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNB1	NM_002074.5	c.233A>G	p.Lys78Arg	missense_variant	6/12	ENST00000378609.9	NP_002065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB1	ENST00000378609.9	c.233A>G	p.Lys78Arg	missense_variant	6/12	1	NM_002074.5	ENSP00000367872.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 42 Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 20, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 02, 2019	This variant was identified as de novo (maternity and paternity confirmed). -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 28, 2024	PS2_Very Strong, PS4, PM1, PM2, PM6, PP2 -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Oct 07, 2019	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] -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 27, 2019	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] -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 03, 2023	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. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2018

- -

Hypotonia;C0036572:Seizure;C0038379:Strabismus;C0232466:Feeding difficulties;C0456070:Growth delay;C0557874:Global developmental delay;C1860834:Infantile muscular hypotonia;C4023476:EEG with generalized epileptiform discharges Pathogenic:1

Pathogenic, no assertion criteria provided

research

Genomics And Bioinformatics Analysis Resource, Columbia University

Feb 10, 2016

- -

Global developmental delay-neuro-ophthalmological abnormalities-seizures-intellectual disability syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Oct 04, 2022

PS4;PM1;PM2_supporting;PM6;PP2;PP3 -

Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 05, 2016

- -

GNB1-related disorder Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	0.0040	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T;T;T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.53	D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.28	N;N;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	.;D;D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.053	.;T;D;D;D
Sift4G	Benign	0.20	T;T;.;.;.
Polyphen		0.85	P;P;.;.;.
Vest4		0.87
MutPred		0.47		Loss of methylation at K78 (P = 0.0179);Loss of methylation at K78 (P = 0.0179);.;Loss of methylation at K78 (P = 0.0179);Loss of methylation at K78 (P = 0.0179);
MVP		0.72
MPC		2.4
ClinPred		0.96	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312823; hg19: chr1-1737948;