Submissions for variant NM_005458.8(GABBR2):c.1699G>A (p.Ala567Thr)

dbSNP: rs922847767

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Choi Lab, Seoul National University	RCV000515463	SCV000611091	pathogenic	Rett syndrome	2017-09-22	criteria provided, single submitter	case-control	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 γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes.
Ambry Genetics	RCV000622956	SCV000741708	pathogenic	Inborn genetic diseases	2016-08-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061069	SCV001225797	pathogenic	Epileptic encephalopathy	2023-11-28	criteria provided, single submitter	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.
CeGaT Center for Human Genetics Tuebingen	RCV001200540	SCV001371531	pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001200540	SCV001430910	pathogenic	not provided	2020-07-28	criteria provided, single submitter	clinical testing	PS2, PS4, PP3, PM2
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001200540	SCV001447451	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000590831	SCV002012064	pathogenic	Neurodevelopmental disorder with poor language and loss of hand skills	2021-10-02	criteria provided, single submitter	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000590831	SCV002764712	pathogenic	Neurodevelopmental disorder with poor language and loss of hand skills	2020-11-03	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003392345	SCV004046181	pathogenic	GABBR2-related disorder		criteria provided, single submitter	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.
OMIM	RCV000590831	SCV000700066	pathogenic	Neurodevelopmental disorder with poor language and loss of hand skills	2018-03-15	no assertion criteria provided	literature only
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000590831	SCV004099400	pathogenic	Neurodevelopmental disorder with poor language and loss of hand skills	2023-10-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003392345	SCV004110460	pathogenic	GABBR2-related disorder	2024-07-22	no assertion criteria provided	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.