3-11026248-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003042.4(SLC6A1):c.967G>T(p.Val323Phe) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V323I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC6A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.967G>T	p.Val323Phe	missense_variant	10/16	ENST00000287766.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.967G>T	p.Val323Phe	missense_variant	10/16	1	NM_003042.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myoclonic-atonic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 06, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SLC6A1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 323 of the SLC6A1 protein (p.Val323Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.82	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	0.45	D
MutationAssessor	Uncertain	2.7	M;M;M;M;M;.;M;.;M;M;M;M;.;M;M;M;.;M;M;M;.;M;M;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
Polyphen		1.0	D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.;.
Vest4		0.95
MutPred		0.56		Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);.;Loss of catalytic residue at V323 (P = 0.167);.;Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);.;Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);.;Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);.;Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);Loss of catalytic residue at V323 (P = 0.167);
MVP		0.95
MPC		2.5
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.48
gMVP		0.97

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

Other links and lift over

dbSNP: rs1403165900; hg19: chr3-11067934;