NM_002074.5:c.301A>G

Variant names:

• chr1-1804548-T-C
• rs869312825
• NM_002074.5:c.301A>G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_002074.5(GNB1):​c.301A>G​(p.Met101Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M101I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.84

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_002074.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GNB1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 3.8328 (above the threshold of 3.09). Trascript score misZ: 3.4817 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 42.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 1-1804548-T-C is Pathogenic according to our data. Variant chr1-1804548-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 224717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1804548-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB1	NM_002074.5	c.301A>G	p.Met101Val	missense_variant	Exon 7 of 12	ENST00000378609.9	NP_002065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB1	ENST00000378609.9	c.301A>G	p.Met101Val	missense_variant	Exon 7 of 12	1	NM_002074.5	ENSP00000367872.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 42 Pathogenic:4 Other:1

Jul 16, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Wangler Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense GNB1 variant at c.301A>G(p.M101V) was discovered on exome through the Texome Project (R01HG011795). It was reported in individuals with Intellectual developmental disorder, autosomal dominant 42 (PMID:27108799, 30194818) (PS4). This variant has not been observed in gnomAD (PM2). The variant was de novo (PS2). We classify this variant as pathogenic. -

Nov 02, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 21, 2018

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Nov 18, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with significantly reduced plasma membrane expression (PMID: 34522861); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27108799, 30194818, 34646230, 36324816, 32134617, 38596856, 35599849, 34522861) -

Feb 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 101 of the GNB1 protein (p.Met101Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability (PMID: 27108799). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 224717). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

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

May 05, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hypotonia;C0036572:Seizure;C0270834:Focal impaired awareness seizure;C0454641:Expressive language delay;C0494475:Bilateral tonic-clonic seizure;C0557874:Global developmental delay;C1836830:Developmental regression;C3714756:Intellectual disability;C4021219:Multifocal epileptiform discharges;C4023476:EEG with generalized epileptiform discharges Pathogenic:1

Feb 10, 2016

Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T;T;T;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.2	M;.;M;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	.;.;D;D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	.;.;D;D;D;D
Sift4G	Uncertain	0.023	D;T;D;.;.;.
Polyphen		0.52	P;.;P;.;.;.
Vest4		0.90
MutPred		0.63		Loss of catalytic residue at M101 (P = 0.0833);.;Loss of catalytic residue at M101 (P = 0.0833);.;Loss of catalytic residue at M101 (P = 0.0833);Loss of catalytic residue at M101 (P = 0.0833);
MVP		0.93
MPC		2.4
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.61

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: rs869312825; hg19: chr1-1735987;