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.
ClinVar Genomic variation as it relates to human health
NM_005458.8(GABBR2):c.1699G>A (p.Ala567Thr)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(12)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005458.8(GABBR2):c.1699G>A (p.Ala567Thr)
Variation ID: 446211 Accession: VCV000446211.41
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q22.33 9: 98371535 (GRCh38) [ NCBI UCSC ] 9: 101133817 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 15, 2017 Oct 20, 2024 Nov 28, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_005458.8:c.1699G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005449.5:p.Ala567Thr missense NC_000009.12:g.98371535C>T NC_000009.11:g.101133817C>T NG_016426.1:g.342663G>A - Protein change
- A567T
- Other names
-
GABBR2
- Canonical SPDI
- NC_000009.12:98371534:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
effect on protein activity; Variation Ontology [ VariO:0053]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GABBR2 | - | - |
GRCh38 GRCh37 |
938 | 1021 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 22, 2017 | RCV000515463.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 3, 2016 | RCV000622956.3 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 2, 2021 | RCV000590831.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 28, 2023 | RCV001061069.7 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2020 | RCV001200540.27 | |
|
GABBR2-related disorder
|
Pathogenic (2) |
criteria provided, single submitter
|
- | RCV003392345.6 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 22, 2017)
|
criteria provided, single submitter
Method: case-control, research, in vitro, in vivo
|
Rett syndrome
(Autosomal dominant inheritance)
Affected status: not applicable, yes
Allele origin:
de novo,
not applicable
|
Choi Lab, Seoul National University
Accession: SCV000611091.1
First in ClinVar: Nov 15, 2017 Last updated: Nov 15, 2017 |
Comment:
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 … (more)
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. (less)
Observation 1:
Clinical Features:
Rett-like phenotype (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Asian
Geographic origin: South Korea
Observation 2:
Clinical Features:
Rett-like phenotype (present)
Age: 20-29 years
Sex: male
Ethnicity/Population group: European
Geographic origin: United States of America
Observation 3:
Clinical Features:
Rett-like phenotype (present)
Age: 10-19 years
Sex: male
Ethnicity/Population group: European
Geographic origin: United States of America
Observation 4:
Sex: mixed
Comment on evidence:
1. The addition of GABA and the GABABR-specific agonist baclofen to the culture media induced a 10-fold increase in receptor activity when a wild-type (GABBR2 … (more)
1. The addition of GABA and the GABABR-specific agonist baclofen to the culture media induced a 10-fold increase in receptor activity when a wild-type (GABBR2 wild-type) receptor was introduced. 2. However, GABBR2 mutant (A567T) showed significantly lowered agonist-induced activity (approximately 30% of wild type), suggesting that the mutation exerts a hypomorphic effect through a dominant-negative mechanism. 3. Interestingly, cotransfection of each EE mutation construct (GABBR2 (S695I) or GABBR2 (I705N)) further reduced the receptor activities, raising the possibility that the major distinction between RTT- and EE-causing var- iants is the receptor activity. 4. Basal receptor activities did not display a significant difference, suggesting that the abnormal receptor functions are agonist dependent. (less)
Observation 5:
Sex: mixed
Comment on evidence:
1. hGABBR2 (A567T) expression caused abnormal swimming patterns and increased frequencies of seizure-like behavior compared to control or wild-type–injected animals 2. The addition of baclofen … (more)
1. hGABBR2 (A567T) expression caused abnormal swimming patterns and increased frequencies of seizure-like behavior compared to control or wild-type–injected animals 2. The addition of baclofen to the bath marginally repressed the seizure-like behavior and swimming distance phenotypes, indicating that the drug can partially de-repress GABABR-mediated inhibitory signaling in these animals. 3. This mild rescue effect was not recapitulated by the addition of a GABA antagonist. (less)
|
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Pathogenic
(Jul 28, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV001430910.1
First in ClinVar: Aug 28, 2020 Last updated: Aug 28, 2020 |
Comment:
PS2, PS4, PP3, PM2
|
|
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447451.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Microcephaly (present) , Motor stereotypies (present) , Global developmental delay (present)
Sex: female
|
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with poor language and loss of hand skills
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002012064.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Cortical dysplasia (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Hypotelorism (present) , Generalized … (more)
Cortical dysplasia (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Hypotelorism (present) , Generalized hypotonia (present) , Intellectual disability (present) , J-shaped sella turcica (present) , Intellectual disability, mild (present) , Leukodystrophy (present) , Long nose (present) , Macrocephaly (present) , Protruding ear (present) , Prominent forehead (present) , Delayed speech and language development (present) , Motor stereotypies (present) , Skeletal dysplasia (present) (less)
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Pathogenic
(Nov 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with poor language and loss of hand skills
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764712.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Motor stereotypies (present) , Dystonic disorder (present) , Absent speech (present)
|
|
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Pathogenic
(Aug 03, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741708.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian
Observation 2:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Nov 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Epileptic encephalopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001225797.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
|
|
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Pathogenic
(Apr 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001371531.24
First in ClinVar: Jul 16, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
GABBR2-related disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046181.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
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, … (more)
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. (less)
|
|
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Pathogenic
(Mar 15, 2018)
|
no assertion criteria provided
Method: literature only
|
NEURODEVELOPMENTAL DISORDER WITH POOR LANGUAGE AND LOSS OF HAND SKILLS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000700066.1
First in ClinVar: Mar 20, 2018 Last updated: Mar 20, 2018 |
Comment on evidence:
In a 19-year-old Portuguese woman (patient 9) with neurodevelopmental disorder with poor speech and loss of hand skills (NDPLHS; 617903), Lopes et al. (2016) identified … (more)
In a 19-year-old Portuguese woman (patient 9) with neurodevelopmental disorder with poor speech and loss of hand skills (NDPLHS; 617903), Lopes et al. (2016) identified a de novo heterozygous c.1699G-A transition (c.1699G-A, NM_005458) in the GABBR2 gene, resulting in an ala567-to-thr (A567T) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 135) database. Functional studies of the variant and studies of patient cells were not performed. The patient was part of a cohort of 19 Portuguese patients with a clinical phenotype similar to Rett syndrome (RTT; 312750) who underwent exome sequencing. Hamdan et al. (2017) noted that the A567T mutation occurs in transmembrane 3 of GABBR2. Yoo et al. (2017) identified a de novo heterozygous A567T mutation in 2 unrelated Korean patients (RTT01-1 and RTT02-1) with NDPLHS. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were found in a study of 34 Korean patients with a Rett-like phenotype who did not carry mutations in the MECP2 gene (300005). The mutation was not found in the 1000 Genomes Project or ExAC databases, or in 1,055 healthy Koreans. A GeneMatcher search enabled the identification of 2 additional patients of European ancestry (RTT83-1 and RTT84-1) who also carried this de novo variant and had a similar disorder. In vitro functional expression studies in HEK293 cells showed that the A567T mutation significantly lowered agonist-induced activity (about 30% of wildtype), suggesting that the mutation exerts a hypomorphic effect through a dominant-negative mechanism. Transfection of the mutation into tadpoles resulted in abnormal swimming patterns and increased frequencies of seizure-like behavior compared to wildtype. The variant could not rescue the defect in tadpoles with morpholino knockdown of the gabbr2 gene, consistent with a loss of function. The addition of baclofen to the water partially rescued the phenotype. (less)
|
|
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Pathogenic
(Oct 30, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Neurodevelopmental disorder with poor language and loss of hand skills
Affected status: yes
Allele origin:
germline
|
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004099400.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
|
|
|
Pathogenic
(Jul 22, 2024)
|
no assertion criteria provided
Method: clinical testing
|
GABBR2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004110460.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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Comment:
Comment:
PS2, PS4, PP3, PM2
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
effect on protein activity
|
|
|
Choi Lab, Seoul National University
Accession: SCV000611091.1
|
|
Comment:
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.
Comment:
PS2, PS4, PP3, PM2
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. | Hamdan FF | American journal of human genetics | 2017 | PMID: 29100083 |
| GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy. | Yoo Y | Annals of neurology | 2017 | PMID: 28856709 |
| Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype. | Lucariello M | Human genetics | 2016 | PMID: 27541642 |
| Identification of novel genetic causes of Rett syndrome-like phenotypes. | Lopes F | Journal of medical genetics | 2016 | PMID: 26740508 |
Text-mined citations for rs922847767 ...
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.