rs1064794981

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_003042.4(SLC6A1):c.1531G>A(p.Val511Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V511L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC6A1
NM_003042.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.84

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

epilepsy with myoclonic atonic seizures
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
myoclonic-astatic epilepsy
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

SLC6A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-11034534-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 813786.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 3-11034534-G-A is Pathogenic according to our data. Variant chr3-11034534-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 421211.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
SLC6A1	NM_003042.4 link	c.1531G>A	p.Val511Met	missense_variant	Exon 15 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10 link	c.1531G>A	p.Val511Met	missense_variant	Exon 15 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722832

African (AFR)

AF:

0.00

AC:

AN:

33260

American (AMR)

AF:

0.00

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

85990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104718

Other (OTH)

AF:

0.00

AC:

AN:

60046

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jan 30, 2025

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in large, multi-ethnic general populations. (gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with autosomal dominant myoclonic-atonic epilepsy, including apparent de novo cases. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 34028503, 38781976) -

Jun 14, 2022

Molecular Genetics laboratory, Necker Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 12, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (Mermer et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29315614, 34028503, 34006619, 31440721, 31302675) -

Epilepsy with myoclonic atonic seizures

Pathogenic:1

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 511 of the SLC6A1 protein (p.Val511Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SLC6A1-related conditions (PMID: 29315614, 31302675; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421211). 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 not expected to disrupt SLC6A1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Neurodevelopmental delay

Pathogenic:1

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Seizure

Pathogenic:1

May 16, 2024

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T;T;T;T;.;T;.;T;T;T;T;.;T;T;T;.;T;T;T;.;T;T;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.080

MetaRNN

Uncertain

0.67

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

-0.12

MutationAssessor

Benign

1.9

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

PhyloP100

7.8

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.0

.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.0070

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

Sift4G

Uncertain

0.0080

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

Polyphen

0.96

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

Vest4

0.58

MutPred

0.46

Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);.;Loss of catalytic residue at V511 (P = 0.0516);.;Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);.;Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);.;Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);.;Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);Loss of catalytic residue at V511 (P = 0.0516);.;

MVP

0.96

MPC

2.0

ClinPred

0.91

GERP RS

5.8

Varity_R

0.36

gMVP

0.88

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over