3-11017434-G-C

Variant names:

• chr3-11017434-G-C
• NM_003042.4:c.223G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_003042.4(SLC6A1):​c.223G>C​(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: Likely pathogenic criteria provided, single submitter P: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 Likely_pathogenic. Variant got 7 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, 0.849
• PP5: Variant 3-11017434-G-C is Pathogenic according to our data. Variant chr3-11017434-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066559.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.223G>C	p.Gly75Arg	missense_variant	Exon 3 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.223G>C	p.Gly75Arg	missense_variant	Exon 3 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy with myoclonic atonic seizures Pathogenic:1

May 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different variant (c.223G>A) giving rise to the same protein effect observed here (p.Gly75Arg) has been determined to be pathogenic (PMID: 28708303). This suggests that this variant is also likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals with SLC6A1-related conditions. This sequence change replaces glycine with arginine at codon 75 of the SLC6A1 protein (p.Gly75Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). -

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	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;T;T
M_CAP	Benign	0.080	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	-0.12	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	0.58
Sift	Uncertain	0.017	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.86	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)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-11059120; COSMIC: COSV55119228; COSMIC: COSV55119228;