rs1057519550

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM2PP2PP5_Very_Strong

The NM_000814.6(GABRB3):​c.372A>C​(p.Leu124Phe) variant causes a missense 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 33)

Consequence

GABRB3
NM_000814.6 missense

Scores

4
10
5

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.03
Variant links:
Genes affected
GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PS1
Transcript NM_000814.6 (GABRB3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRB3. . Gene score misZ: 3.3856 (greater than the threshold 3.09). Trascript score misZ: 4.4544 (greater than threshold 3.09). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. GenCC has associacion of the gene with childhood absence epilepsy, developmental and epileptic encephalopathy, 43, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, epilepsy, childhood absence, susceptibility to, 5.
PP5
Variant 15-26621403-T-G is Pathogenic according to our data. Variant chr15-26621403-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GABRB3NM_000814.6 linkc.372A>C p.Leu124Phe missense_variant 4/9 ENST00000311550.10 NP_000805.1 P28472-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GABRB3ENST00000311550.10 linkc.372A>C p.Leu124Phe missense_variant 4/91 NM_000814.6 ENSP00000308725.5 P28472-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Epileptic encephalopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingNeurogenetics Laboratory - MEYER, AOU MeyerNov 16, 2016- -
Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 07, 2024This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 124 of the GABRB3 protein (p.Leu124Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 27864847, 34698933, 35383156). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375532). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GABRB3 protein function. Experimental studies have shown that this missense change affects GABRB3 function (PMID: 35383156). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
.;T;.;.;.;.;.;.;.
Eigen
Benign
0.012
Eigen_PC
Benign
-0.019
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.96
.;D;D;D;D;.;D;D;.
M_CAP
Uncertain
0.17
D
MetaRNN
Uncertain
0.58
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.40
T
MutationAssessor
Uncertain
2.2
.;M;.;.;M;.;.;.;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-2.2
.;N;.;N;N;.;.;N;N
REVEL
Uncertain
0.57
Sift
Uncertain
0.022
.;D;.;D;D;.;.;D;D
Sift4G
Uncertain
0.013
D;D;D;D;D;.;.;D;D
Polyphen
0.96, 0.95
.;D;.;P;P;.;.;.;.
Vest4
0.80
MutPred
0.51
.;.;.;Gain of catalytic residue at L180 (P = 0.0058);.;.;.;.;.;
MVP
0.95
MPC
2.5
ClinPred
0.89
D
GERP RS
0.95
Varity_R
0.67
gMVP
0.90

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057519550; hg19: chr15-26866550; API