rs876657400

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_003042.4(SLC6A1):c.889G>A(p.Gly297Arg) 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

SLC6A1
NM_003042.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 9.74

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.989

PP5

Variant 3-11025812-G-A is Pathogenic according to our data. Variant chr3-11025812-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 192369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-11025812-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.889G>A	p.Gly297Arg	missense_variant	Exon 9 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.889G>A	p.Gly297Arg	missense_variant	Exon 9 of 16	1	NM_003042.4	ENSP00000287766.4		P30531

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Oct 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on GABA uptake activity and a significant reduction in GAT-1 cell surface expression (Mermer et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25865495, 33004838, 35295842, 29895856, 28191889, 34653234, 34006619, 34028503) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2019

Laboratoire Génétique Moléculaire, CHRU TOURS

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epilepsy with myoclonic atonic seizures

Pathogenic:4Other:1

May 07, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 10, 2019

Genetics Laboratory - UDIAT Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 297 of the SLC6A1 protein (p.Gly297Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SLC6A1-related conditions (PMID: 25865495, 34653234). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 192369). 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. For these reasons, this variant has been classified as Pathogenic. -

Jun 23, 2021

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant reported in multiple GenomeConnect participants by multiple clinical testing laboratories. Variant classified by all laboratories as Pathogenic and reported most recently on 08-16-2019 by GeneDx and 12-12-2018 by UCLA Laboratory Genetics and Genomics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

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

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

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

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

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

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

3.3

M;M;M;M;M;.;M;.;M;M;M;M;.;M;M;M;.;M;M;M;.;M;M;M;.;.

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.3

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

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

0.86

P;P;P;P;P;.;P;.;P;P;P;P;.;P;P;P;.;P;P;P;.;P;P;P;.;.

Vest4

0.98

MutPred

0.93

Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);.;Gain of methylation at G297 (P = 0.0143);.;Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);.;Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);.;Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);.;Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);Gain of methylation at G297 (P = 0.0143);

MVP

0.99

MPC

2.0

ClinPred

1.0

GERP RS

4.8

Varity_R

0.92

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: 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