Submissions for variant NM_003042.4(SLC6A1):c.919G>A (p.Gly307Arg)

dbSNP: rs1553689696

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497644	SCV000589838	pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27541642, 31981491, 33004838, 35295842)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003444559	SCV001214658	pathogenic	Epilepsy with myoclonic atonic seizures	2024-02-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 307 of the SLC6A1 protein (p.Gly307Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SLC6A1-related conditions (PMID: 27541642; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 432150). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV002279277	SCV002564504	pathogenic	Neurodevelopmental disorder	2022-05-13	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003444559	SCV002767428	pathogenic	Epilepsy with myoclonic atonic seizures	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with myoclonic-atonic epilepsy (MIM#616421). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated transmembrane helical 6 region (UniProt, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic/pathogenic in multiple patients, including de novo in a patient with seizures, global developmental delay, absent speech and 2-3 toe syndactyly and a patient with Rett-like phenotype (ClinVar, Deciphering Developmental Disorders Study and PMID: 27541642). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (LABIDs). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, University of Leipzig Medical Center	RCV003444559	SCV003804651	likely pathogenic	Epilepsy with myoclonic atonic seizures	2023-02-02	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS4_MOD, PM1, PM2_SUP, PP3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003444559	SCV004562573	pathogenic	Epilepsy with myoclonic atonic seizures	2023-09-25	criteria provided, single submitter	clinical testing	The SLC6A1 c.919G>A; p.Gly307Arg variant (rs1553689696; ClinVar variation ID: 432150) is reported in the literature as a recurrent de novo variant identified in multiple individuals included in cohorts of epilepsy patients (Johannesen 2023, Kalvakuntla 2023, Lucariello 2016, Piniella 2023). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.907). Based on the available information, this variant is considered pathogenic. References: Johannesen KM et al. The phenotypic presentation of adult individuals with SLC6A1-related neurodevelopmental disorders. Front Neurosci. 2023 Aug 17;17:1216653. PMID: 37662110 Kalvakuntla S et al. Patterns of developmental regression and associated clinical characteristics in SLC6A1-related disorder. Front Neurosci. 2023 Feb 21;17:1024388. PMID: 36895422 Lucariello M et al. Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype. Hum Genet. 2016 Dec;135(12):1343-1354. PMID: 27541642 Piniella D et al. Experimental and Bioinformatic Insights into the Effects of Epileptogenic Variants on the Function and Trafficking of the GABA Transporter GAT-1. Int J Mol Sci. 2023 Jan 4;24(2):955 PMID: 36674476
Department of Developmental Neurology, Medical University of Gdańsk	RCV003444559	SCV004101035	not provided	Epilepsy with myoclonic atonic seizures		no assertion provided	phenotyping only