rs879253748

Positions:

• chr5-161897250-TC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000393943.10(GABRA1):​c.1200del​(p.Lys401SerfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA1 ENST00000393943.10 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.612

Genes affected

GABRA1 (HGNC:4075): (gamma-aminobutyric acid type A receptor subunit alpha1) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.125 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-161897250-TC-T is Pathogenic according to our data. Variant chr5-161897250-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 242830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-161897250-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.1200del	p.Lys401SerfsTer25	frameshift_variant	10/10	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.1200del	p.Lys401SerfsTer25	frameshift_variant	10/10	1	NM_001127644.2	ENSP00000377517	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 19 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Jul 03, 2016

The herewith reported de novo deletion of one base pair (c.1200del) in the last exon of GABRA1 is located downstream of the last splice junction and thus probably escapes nonsense-mediated mRNA decay. The variant is predicted to cause frameshifting and a premature translational stop codon (p.(Lys401Serfs*25)), changing or truncating the last 56 residues of the protein and thus lacking part of the intracellular loop between the last two transmembrane domains and the complete C-terminal transmembrane domain. In the literature, similar variants in GABRA1 and also in other GABA-A subunits have already been associated with disease. Functional studies for these variants could demonstrate a disrupted surface expression, hence leading to a change in subunit composition with reduction of GABA-A mediated inhibition resulting in a predisposition to seizures. Taken together the de novo status of the herewith identified GABRA1 variant c.1200del, the matching phenotype of the patient and the descriptions in the literature argue for the pathogenicity of this variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs879253748; hg19: chr5-161324256;