VCV001804152.1 - ClinVar

NM_001470.4(GABBR1):c.1603G>A (p.Ala535Thr)

Germline

Classification

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.

(2)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001470.4(GABBR1):c.1603G>A (p.Ala535Thr)

Variation ID: 1804152 Accession: VCV001804152.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p22.1 6: 29612578 (GRCh38) [ NCBI UCSC ] 6: 29580355 (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	Dec 24, 2022	Sep 16, 2023	Dec 6, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001470.4:c.1603G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001461.1:p.Ala535Thr	missense
NM_001319053.2:c.1072G>A	NP_001305982.1:p.Ala358Thr	missense
NM_021903.3:c.1252G>A	NP_068703.1:p.Ala418Thr	missense
NM_021904.4:c.1417G>A	NP_068704.2:p.Ala473Thr	missense
NC_000006.12:g.29612578C>T
NC_000006.11:g.29580355C>T
NG_029101.1:g.25608G>A

... more HGVS ... less HGVS

Protein change

A358T, A418T, A473T, A535T

Other names

Canonical SPDI

NC_000006.12:29612577:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

OMIM: 603540.0001 VarSome

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
Gene	OMIM	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.
GABBR1		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	74	83

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.
Delayed speech and language development Global developmental delay Intellectual disability	Likely pathogenic (1)	criteria provided, single submitter	Dec 6, 2022	RCV002468890.4
Neurodevelopmental disorder with language delay and variable cognitive abnormalities	Pathogenic (1)	no assertion criteria provided	Sep 11, 2023	RCV003327570.3

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.
Likely pathogenic (Dec 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Delayed speech and language development Intellectual disability Global developmental delay Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002765109.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 36103875 Comment: This variant was identified as de novo (maternity and paternity confirmed).
Pathogenic (Sep 11, 2023)	no assertion criteria provided Method: literature only	NEURODEVELOPMENTAL DISORDER WITH LANGUAGE DELAY AND VARIABLE COGNITIVE ABNORMALITIES Affected status: not provided Allele origin: germline	OMIM Accession: SCV004034298.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023	Publications: Cediel, M. L., Stawarski, M., (more...) Cediel, M. L., Stawarski, M., Blanc, X., Noskova, L., Magner, M., Platzer, K., Gburek-Augustat, J., Baldridge, D., Constantino, J. N., Ranza, E., Bettler, B., Antonarakis, S. E. GABBR1 monoallelic de novo variants linked to neurodevelopmental delay and epilepsy. Am. J. Hum. Genet. 109: 1885-1893, 2022. Comment on evidence: In a 2.5-year-old girl (P1) with neurodevelopmental disorder with language delay and variable cognitive abnormalities (NEDLC; 620502), Cediel et al. (2022) identified a de novo … (more) In a 2.5-year-old girl (P1) with neurodevelopmental disorder with language delay and variable cognitive abnormalities (NEDLC; 620502), Cediel et al. (2022) identified a de novo heterozygous c.1603G-A transition (c.1603G-A, NM_001470.4) in the GABBR1 gene, resulting in an ala535-to-thr (A535T) substitution at a conserved residue in the linker between the VFTD and TM1 domains. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Detailed in vitro functional expression studies of the variant in HEK293 cells showed that the assembled receptor was expressed normally on the cell membrane, but the variant interfered with coupling of agonist binding to G protein activation (decreased Emax). A dominant-negative effect was not observed. The findings were consistent with a loss-of-function effect that most likely tips the excitation/inhibition balance in the central nervous system towards more excitation. (less)

Citation text

Cediel, M. L., Stawarski, M., Blanc, X., Noskova, L., Magner, M., Platzer, K., Gburek-Augustat, J., Baldridge, D., Constantino, J. N., Ranza, E., Bettler, B., Antonarakis, S. E. GABBR1 monoallelic de novo variants linked to neurodevelopmental delay and epilepsy. Am. J. Hum. Genet. 109: 1885-1893, 2022.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
GABBR1 monoallelic de novo variants linked to neurodevelopmental delay and epilepsy.	Cediel ML	American journal of human genetics	2022	PMID: 36103875

Text-mined citations for this variant ...

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001470.4(GABBR1):c.1603G>A (p.Ala535Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...