3-11034534-G-T

Variant names:

• chr3-11034534-G-T
• rs1064794981
• NM_003042.4:c.1531G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP5_Moderate

The NM_003042.4(SLC6A1):​c.1531G>T​(p.Val511Leu) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V511M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.84
• Publications: 0 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, Illumina, G2P
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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-A is described in ClinVar as Pathogenic. ClinVar VariationId is 421211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 3-11034534-G-T is Pathogenic according to our data. 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003042.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	NM_003042.4	MANE Select	c.1531G>T	p.Val511Leu	missense	Exon 15 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.1531G>T	p.Val511Leu	missense	Exon 15 of 16	NP_001335179.1	P30531
	SLC6A1	NM_001348251.2		c.1171G>T	p.Val391Leu	missense	Exon 15 of 16	NP_001335180.1	A0A2R8Y4I3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	ENST00000287766.10	TSL:1 MANE Select	c.1531G>T	p.Val511Leu	missense	Exon 15 of 16	ENSP00000287766.4	P30531
	SLC6A1	ENST00000698198.1		c.1603G>T	p.Val535Leu	missense	Exon 13 of 14	ENSP00000513602.1	A0A8V8TMZ9
	SLC6A1	ENST00000644803.1		c.1558G>T	p.Val520Leu	missense	Exon 13 of 14	ENSP00000494469.1	A0A2R8YDD5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Epilepsy with myoclonic atonic seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.40
Sift	Benign	0.049	D
Sift4G	Benign	0.070	T
Polyphen		0.81	P
Vest4		0.59
MutPred		0.46		Gain of helix (P = 0.2294)
MVP		0.92
MPC		2.0
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.35
gMVP		0.92
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1064794981; hg19: chr3-11076220;