NM_003042.4:c.131G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_003042.4(SLC6A1):c.131G>A(p.Arg44Gln) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SLC6A1
NM_003042.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.86

Variant links:

Genes affected

SLC6A1 (HGNC:11042): (solute carrier family 6 member 1) The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals. [provided by RefSeq, Jan 2017]

SLC6A1 links:

SLC6A1-AS1 (HGNC:40546): (SLC6A1 antisense RNA 1)

SLC6A1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-11017341-C-T is described in Lovd as [Likely_pathogenic].

PP2

Missense variant in the SLC6A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 67 curated pathogenic missense variants (we use a threshold of 10). The gene has 76 curated benign missense variants. Gene score misZ: 4.1766 (above the threshold of 3.09). Trascript score misZ: 4.9229 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonic-atonic epilepsy, myoclonic-astatic epilepsy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 3-11017342-G-A is Pathogenic according to our data. Variant chr3-11017342-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 192368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-11017342-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4 link	c.131G>A	p.Arg44Gln	missense_variant	Exon 3 of 16	ENST00000287766.10	NP_003033.3	A0A024R2K8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10 link	c.131G>A	p.Arg44Gln	missense_variant	Exon 3 of 16	1	NM_003042.4	ENSP00000287766.4		P30531

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epilepsy with myoclonic atonic seizures

Pathogenic:3

May 01, 2016

Baylor Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Our laboratory reported two molecular diagnoses in ANKRD11 (NM_013275.5:c.3122C>A) and SLC6A1 (NM_003042.3:c.131G>A) in an individual with prematurity, delayed motor milestones, delayed speech, developmental regression, hearing loss, axial hypotonia, distal spasticity, seizure disorder, dysmorphic features, failure to thrive, feeding difficulties, and eye anomalies. -

Jun 12, 2024

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 glutamine, which is neutral and polar, at codon 44 of the SLC6A1 protein (p.Arg44Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with 34006619, clinical features of SLC6A1-related conditions, and/or myoclonic-atonic epilepsy (PMID: 25865495, 27959697, 28191889, 34006619). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 192368). 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 SLC6A1 protein function. This variant disrupts the p.Arg44 amino acid residue in SLC6A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25865495, 27959697, 28191889). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 07, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Aug 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in heterozygous state in one individual in an autism and intellectual disability cohort in published literature (Stessman et al., 2017); 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: 29086036, 27959697, 25865495, 33004838, 35295842, 28191889) -

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant epilepsy

Pathogenic:1

Mar 23, 2023

Rare Disease Center, Seoul National University Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.6

H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;H;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.5

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0010

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.

Vest4

0.91

MutPred

0.91

Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);

MVP

0.99

MPC

2.3

ClinPred

1.0

GERP RS

4.4

Varity_R

0.84

gMVP

0.89

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over