rs794726859

chr3-11017342-G-Achr3-11017342-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003042.4(SLC6A1):c.131G>A(p.Arg44Gln) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.86

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 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 7 uncertain in NM_003042.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-11017341-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SLC6A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 3-11017342-G-A is Pathogenic according to our data. Variant chr3-11017342-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 192368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-11017342-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.131G>A	p.Arg44Gln	missense_variant	3/16	ENST00000287766.10
SLC6A1-AS1	NR_046647.1	n.105+1778C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.131G>A	p.Arg44Gln	missense_variant	3/16	1	NM_003042.4	P1
SLC6A1-AS1	ENST00000414969.2	n.105+1778C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2022	Reported in heterozygous state in one individual in an autism and intellectual disability cohort in published literature (Stessman et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29086036, 27959697, 25865495, 33004838, 35295842, 28191889) -

Myoclonic-astatic epilepsy Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	May 01, 2016	Our laboratory reported two molecular diagnoses in ANKRD11 (NM_013275.5:c.3122C>A) and SLC6A1 (NM_003042.3:c.131G>A) in an individual with prematurity, delayed motor milestones, delayed speech, developmental regression, hearing loss, axial hypotonia, distal spasticity, seizure disorder, dysmorphic features, failure to thrive, feeding difficulties, and eye anomalies. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 07, 2015	- -

Autosomal dominant epilepsy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Rare Disease Center, Seoul National University Hospital

Mar 23, 2023

- -

Myoclonic-atonic epilepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC6A1 protein function. ClinVar contains an entry for this variant (Variation ID: 192368). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg44 amino acid residue in SLC6A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25865495, 27959697, 28191889). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This missense change has been observed in individual(s) with 34006619, clinical features of SLC6A1-related conditions, and/or myoclonic-atonic epilepsy (PMID: 25865495, 27959697, 28191889, 34006619). 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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 44 of the SLC6A1 protein (p.Arg44Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.6	H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;H;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.
Vest4		0.91
MutPred		0.91		Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);Loss of MoRF binding (P = 0.0502);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.84
gMVP		0.89

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: rs794726859; hg19: chr3-11059028; COSMIC: COSV55116463; COSMIC: COSV55116463;