chr3-11034534-G-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PM5 PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000570338: Published functional studies demonstrate a damaging effect (Mermer et al., 2021); SCV000615329: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID:34028503, 38781976)". 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.84
• Publications: 8 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000570338: Published functional studies demonstrate a damaging effect (Mermer et al., 2021); SCV000615329: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 34028503, 38781976)
• 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.

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>A	p.Val511Met	missense	Exon 15 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.1531G>A	p.Val511Met	missense	Exon 15 of 16	NP_001335179.1	P30531
	SLC6A1	NM_001348251.2		c.1171G>A	p.Val391Met	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>A	p.Val511Met	missense	Exon 15 of 16	ENSP00000287766.4	P30531
	SLC6A1	ENST00000698198.1		c.1603G>A	p.Val535Met	missense	Exon 13 of 14	ENSP00000513602.1	A0A8V8TMZ9
	SLC6A1	ENST00000644803.1		c.1558G>A	p.Val520Met	missense	Exon 13 of 14	ENSP00000494469.1	A0A2R8YDD5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453188 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722832

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 85990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104718

Other (OTH) AF: 0.00 AC: 0 AN: 60046

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Epilepsy with myoclonic atonic seizures (1)
1	-	-	Neurodevelopmental delay (1)
1	-	-	Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.9	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.96	D
Vest4		0.58
MutPred		0.46		Loss of catalytic residue at V511 (P = 0.0516)
MVP		0.96
MPC		2.0
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.36
gMVP		0.88
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064794981; hg19: chr3-11076220; COSMIC: COSV55117205; COSMIC: COSV55117205;