3-11026281-G-T

Variant names:

• chr3-11026281-G-T
• rs749240316
• NM_003042.4:c.1000G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_003042.4(SLC6A1):​c.1000G>T​(p.Ala334Ser) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A334T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 9.74
• Publications: 9 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_003042.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-11026281-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 656334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.1000G>T	p.Ala334Ser	missense_variant	Exon 10 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.1000G>T	p.Ala334Ser	missense_variant	Exon 10 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

SLC6A1-related neurodevelopmental condition Pathogenic:1

Jul 23, 2024

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Nov 04, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; A different missense variant at this residue (A334P) has been reported in association with myoclonic-atonic seizures (Carvill et al., 2015) -

Epilepsy with myoclonic atonic seizures Benign:1

May 22, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T;T;T;.;T;.;T;T;T;T;.;T;T;T;.;T;T;T;.;T;T;T;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;D;.;.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.87	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	-0.039	T
MutationAssessor	Benign	1.5	L;L;L;L;L;.;L;.;L;L;L;L;.;L;L;L;.;L;L;L;.;L;L;L;.;.
PhyloP100		9.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.62
Sift	Benign	0.23	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.19	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.;.
Vest4		0.82
MutPred		0.83		Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);.;Gain of glycosylation at A334 (P = 0.0264);.;Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);.;Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);.;Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);.;Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);Gain of glycosylation at A334 (P = 0.0264);
MVP		0.86
MPC		2.0
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.28
gMVP		0.77
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs749240316; hg19: chr3-11067967;