dbSNP rs922847767: GABBR2:p.Ala567Thr (chr9-98371535-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_005458.8(GABBR2):c.1699G>A(p.Ala567Thr) 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 (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GABBR2
NM_005458.8 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.51

Variant links:

Genes affected

GABBR2 (HGNC:4507): (gamma-aminobutyric acid type B receptor subunit 2) The multi-pass membrane protein encoded by this gene belongs to the G-protein coupled receptor 3 family and GABA-B receptor subfamily. The GABA-B receptors inhibit neuronal activity through G protein-coupled second-messenger systems, which regulate the release of neurotransmitters, and the activity of ion channels and adenylyl cyclase. This receptor subunit forms an active heterodimeric complex with GABA-B receptor subunit 1, neither of which is effective on its own. Allelic variants of this gene have been associated with nicotine dependence.[provided by RefSeq, Jan 2010]

GABBR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.87

PP5

Variant 9-98371535-C-T is Pathogenic according to our data. Variant chr9-98371535-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 446211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-98371535-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8 link	c.1699G>A	p.Ala567Thr	missense_variant	Exon 12 of 19	ENST00000259455.4	NP_005449.5	O75899H9NIL8
GABBR2	XM_017015331.3 link	c.1405G>A	p.Ala469Thr	missense_variant	Exon 11 of 18		XP_016870820.1
GABBR2	XM_005252316.6 link	c.925G>A	p.Ala309Thr	missense_variant	Exon 10 of 17		XP_005252373.1
GABBR2	XM_017015332.3 link	c.925G>A	p.Ala309Thr	missense_variant	Exon 9 of 16		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4 link	c.1699G>A	p.Ala567Thr	missense_variant	Exon 12 of 19	1	NM_005458.8	ENSP00000259455.2		O75899

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726324

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with poor language and loss of hand skills

Pathogenic:4

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 25533962, 28688840 PS2, PS4_M). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 03, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 15, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:3

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS4, PP3, PM2 -

GABBR2-related disorder

Pathogenic:2

Jul 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GABBR2 c.1699G>A variant is predicted to result in the amino acid substitution p.Ala567Thr. This variant has been reported as a recurrent de novo variant in individuals with Rett-syndrome-like phenotypes and non-specified neurodevelopmental disorders (see, for example, Lopes et al. 2016. PubMed ID: 26740508; Lucariello et al. 2016. PubMed ID: 27541642; Table S1, Takata et al. 2018. PubMed ID: 29346770; Yoo et al. 2017. PubMed ID: 28856709). This variant has not been reported in a large population database, indicating this variant is rare. Another missense variant affecting the same amino acid (p.Ala567Val) has been reported in an individual with autism spectrum disorder (Supplementary Data 1, Zhou et al. 2022. PubMed ID: 35982159). This variant is interpreted as pathogenic. -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a de novo heterozygous change in multiple unrelated patients with autism spectrum disorder, motor and language developmental delay, developmental regression, stereotypies, sleep disturbance, and muscular hypotonia with or without epileptic encephalopathy (PMID: 26740508, 27541642, 28191890, 28856709, 28867141, 29346770). A different amino acid change at the same residue (p.Ala567Val) has been observed in individuals with similar clinical phenotype and in at least one of these individuals, this variant was detected to be de novo (Variation ID: 1073462, Invitae internal data). The GABBR2 gene is constrained against variation (Z-score= 4.63 and pLI = 1) and missense variants are a common mechanism of disease (HGMD, ClinVar database). Experimental studies showed that presence of the p.Ala567Thr variant resulted in abnormal protein activity in HEK293 cells without altering protein expression and subcellular localization; furthermore, this variant caused abnormal behaviors in tadpoles (PMID: 28856709). The c.1699G>A (p.Ala567Thr) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1699G>A (p.Ala567Thr) variant is classified as Pathogenic. -

Rett syndrome

Pathogenic:1

Sep 22, 2017

Choi Lab, Seoul National University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control;in vitro;in vivo;research

We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model. GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated Î³-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. -

Inborn genetic diseases

Pathogenic:1

Aug 03, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epileptic encephalopathy

Pathogenic:1

Nov 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 567 of the GABBR2 protein (p.Ala567Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GABBR2-related conditions (PMID: 26740508, 27541642, 28856709). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 446211). 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 GABBR2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GABBR2 function (PMID: 28856709). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.8

L;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.5

D;.

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0060

D;.

Polyphen

1.0

D;.

Vest4

0.75

MutPred

0.67

Gain of MoRF binding (P = 0.1367);.;

MVP

0.85

MPC

1.3

ClinPred

0.98

GERP RS

5.4

Varity_R

0.88

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over