rs1064795852

Positions:

• chr3-11017434-G-A
• chr3-11017434-G-C

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.223G>A​(p.Gly75Arg) variant causes a missense change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 6.65

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-AS1 (HGNC:40546): (SLC6A1 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC6A1. . Gene score misZ: 4.1766 (greater than the threshold 3.09). Trascript score misZ: 4.9229 (greater than threshold 3.09). The gene has 67 curated pathogenic missense variants (we use a threshold of 10). The gene has 76 curated benign missense variants. GenCC has associacion of the gene with myoclonic-atonic epilepsy, myoclonic-astatic epilepsy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85
• PP5: Variant 3-11017434-G-A is Pathogenic according to our data. Variant chr3-11017434-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 422549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.223G>A	p.Gly75Arg	missense_variant	3/16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.223G>A	p.Gly75Arg	missense_variant	3/16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy with myoclonic atonic seizures Pathogenic:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant classified as Pathogenic and reported on 01-27-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	Jan 06, 2017	Intellectual disability, mild; epilepsy (absence seizures); weight stagnation; hypereosinophilia ; no myoclonic-atonic epilepsy -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	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 not expected to disrupt SLC6A1 protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 422549). This missense change has been observed in individual(s) with clinical features of myoclonic-atonic epilepsy (PMID: 28708303, 29315614; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 75 of the SLC6A1 protein (p.Gly75Arg). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2020

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; This variant is associated with the following publications: (PMID: 28708303, 29315614) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
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	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.85	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	-0.19	T
MutationAssessor	Benign	1.4	L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.25	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.017	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.93	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;.;P;P;.;.;.
Vest4		0.84
MutPred		0.74		Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);Gain of methylation at G75 (P = 0.0351);
MVP		0.92
MPC		1.4
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.59
gMVP		0.96

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: rs1064795852; hg19: chr3-11059120;