3-11026281-G-A

Position:

chr3-11026281-G-A

Variant summary

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

The NM_003042.4(SLC6A1):c.1000G>A(p.Ala334Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC6A1
NM_003042.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U: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:

Genome browser will be placed here

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 gene, where missense usually causes diseases (based on misZ statistic), SLC6A1. . Gene score misZ: 4.1766 (greater than the threshold 3.09). Trascript score misZ: 4.9229 (greater than threshold 3.09). The gene has 67 curated pathogenic missense variants (we use a threshold of 10). The gene has 76 curated benign missense variants. GenCC has associacion of the gene with myoclonic-atonic epilepsy, myoclonic-astatic epilepsy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 3-11026281-G-A is Pathogenic according to our data. Variant chr3-11026281-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 656334.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
SLC6A1	NM_003042.4 link	c.1000G>A	p.Ala334Thr	missense_variant	10/16	ENST00000287766.10	NP_003033.3	A0A024R2K8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10 link	c.1000G>A	p.Ala334Thr	missense_variant	10/16	1	NM_003042.4	ENSP00000287766.4		P30531

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251396

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epilepsy with myoclonic atonic seizures

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 20, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with myoclonic-atonic epilepsy (MIM#616421). The phenotypic spectrum associated with this gene includes intellectual disability, autistic spectrum disorders, epilepsy, and other neurological features such as hypotonia and movement disorders (PMID: 37502687). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 37502687) . (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD v2/3 <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions. (I) 0600 - Variant is located in the annotated sodium neurotransmitter symporter family domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ala344Pro) was reported in an individual with myoclonic-atonic epilepsy (PMID: 25865495). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in three unrelated individuals, one with epileptic encephalopathy and the other two with seizures (ClinVar, Invitae correspondence). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro analysis of tranfected cells demonstrated loss of function for this variant (Silva, D.B. et al. (2023)). (SP) 1206 - This variant has been shown to be paternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2023	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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 656334). This missense change has been observed in individuals with clinical features of SLC6A1-related conditions (Invitae). This variant is present in population databases (rs749240316, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the SLC6A1 protein (p.Ala334Thr). -

Seizure;C3714756:Intellectual disability

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

SLC6A1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2024

The SLC6A1 c.1000G>A variant is predicted to result in the amino acid substitution p.Ala334Thr. This variant was reported in an individual with a neurological and/or developmental disorder, but the specific type of disorder was not mentioned (Turro et al. 2020. PubMed ID: 32581362). At PreventionGenetics, this variant was detected in the heterozygous state in an individual with autism spectrum disorder and found to be inherited from a parent with unknown phenotype. Of note, another missense variant, affecting the same amino acid residue (p.Ala334Pro), has been reported to be causative for epilepsy with myoclonic-atonic seizures (Carvill et al. 2015. PubMed ID: 25865495). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.96

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

0.62

MutationAssessor

Pathogenic

3.4

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

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.2

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

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.019

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

Polyphen

1.0

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

Vest4

0.97

MutPred

0.85

Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;Gain of sheet (P = 0.1945);.;Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);

MVP

0.94

MPC

2.2

ClinPred

1.0

GERP RS

5.4

Varity_R

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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