rs886039373

Variant names:

• chr5-161882639-G-A
• rs886039373
• NM_001127644.2:c.641G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_001127644.2(GABRA1):​c.641G>A​(p.Arg214His) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA1 NM_001127644.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.88

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GABRA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.1498 (above the threshold of 3.09). Trascript score misZ: 4.2662 (above the threshold of 3.09). GenCC associations: The gene is linked to juvenile myoclonic epilepsy, developmental and epileptic encephalopathy, 19, epilepsy, idiopathic generalized, susceptibility to, 13, Dravet syndrome, developmental and epileptic encephalopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785
• PP5: Variant 5-161882639-G-A is Pathogenic according to our data. Variant chr5-161882639-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.641G>A	p.Arg214His	missense_variant	Exon 7 of 10	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.641G>A	p.Arg214His	missense_variant	Exon 7 of 10	1	NM_001127644.2	ENSP00000377517.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 19 Pathogenic:5

Jul 05, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2018

Genatak

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 08, 2002

Center of Excellence for Medical Genomics, Chulalongkorn University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Dec 11, 2019

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG evidence PS2, PM2, PP2, PP3, PP5 -

May 10, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PP3 -

not provided Pathogenic:2

Jun 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional study demonstrates a damaging effect due to impaired GABA-A receptor inhibitory function (Johannesen et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27353043, 30185235, 32238909, 27535533, 27521439) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GABRA1: PM2, PM5, PM6, PS4:Moderate, PP2, PP3, PS3:Supporting -

Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13 Pathogenic:1

Dec 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 214 of the GABRA1 protein (p.Arg214His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome-like phenotype (PMID: 27353043). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265162). 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 expected to disrupt GABRA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GABRA1 function (PMID: 27353043). For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy, 19;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP2+PS4_Moderate+PM6_Strong+PM1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;D;D;D;D;D;.;D;.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;.;.;.;.;D;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.7	L;L;L;L;L;L;.;L;.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	.;D;D;D;D;.;.;.;.;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	.;D;D;D;D;.;.;.;.;.
Sift4G	Benign	0.10	.;T;T;T;T;.;.;.;T;.
Polyphen		1.0	D;D;D;D;D;D;.;D;.;D
Vest4		0.79, 0.70, 0.79, 0.79
MutPred		0.51		Gain of disorder (P = 0.1481);Gain of disorder (P = 0.1481);Gain of disorder (P = 0.1481);Gain of disorder (P = 0.1481);Gain of disorder (P = 0.1481);Gain of disorder (P = 0.1481);.;Gain of disorder (P = 0.1481);Gain of disorder (P = 0.1481);Gain of disorder (P = 0.1481);
MVP		0.89
MPC		2.5
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.61
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886039373; hg19: chr5-161309645;