3-11031230-C-G

Variant names:

• chr3-11031230-C-G
• rs1064795099
• NM_003042.4:c.1377C>G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_003042.4(SLC6A1):​c.1377C>G​(p.Ser459Arg) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.52

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 Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SLC6A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 67 curated pathogenic missense variants (we use a threshold of 10). The gene has 76 curated benign missense variants. Gene score misZ: 4.1766 (above the threshold of 3.09). Trascript score misZ: 4.9229 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonic-atonic epilepsy, myoclonic-astatic epilepsy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 3-11031230-C-G is Pathogenic according to our data. Variant chr3-11031230-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 570384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.1377C>G	p.Ser459Arg	missense_variant	Exon 13 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.1377C>G	p.Ser459Arg	missense_variant	Exon 13 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy with myoclonic atonic seizures Pathogenic:2

Oct 09, 2020

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The de novo heterozygous p.Ser459Arg missense variant identified in the SLC6A1 gene has been previously reported in at least one affected individual in the literature [PMID: 29315614]. The p.Ser459Arg variant is absent from gnomAD(V3) database indicating it is an extremely rare allele in the populations represented in this databsase. This variant is reported as Pathogenic in ClinVar (VarID: 570384). The variant affects amoderately conserved reside and is predicted deleterious by multiple in silico prediction tools. Based on the available evidence, the de novo p.Ser459Arg variant in the SLC6A1 gene is assessed as pathogenic. -

Jul 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SLC6A1- related disease (PMID: 29315614; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 570384). 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 expected to disrupt SLC6A1 protein function. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 459 of the SLC6A1 protein (p.Ser459Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;D;.;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.92	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	0.28	D
MutationAssessor	Pathogenic	3.5	H;H;H;H;H;.;H;.;H;H;H;H;.;H;H;H;.;H;H;H;.;H;H;H;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.2	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0040	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.99	D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.
Vest4		0.85
MutPred		0.84		Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;
MVP		0.95
MPC		1.8
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.98

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: rs1064795099; hg19: chr3-11072916;