Submissions for variant NM_003042.4(SLC6A1):c.889G>A (p.Gly297Arg)

dbSNP: rs876657400

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetics Laboratory - UDIAT Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV003444213	SCV000930704	pathogenic	Epilepsy with myoclonic atonic seizures	2019-07-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268638	SCV001447711	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003444213	SCV001581155	pathogenic	Epilepsy with myoclonic atonic seizures	2024-04-03	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 297 of the SLC6A1 protein (p.Gly297Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SLC6A1-related conditions (PMID: 25865495, 34653234). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 192369). 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. For these reasons, this variant has been classified as Pathogenic.
Laboratoire Génétique Moléculaire, CHRU TOURS	RCV001268638	SCV001760758	likely pathogenic	not provided	2019-07-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001268638	SCV001785892	pathogenic	not provided	2022-10-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on GABA uptake activity and a significant reduction in GAT-1 cell surface expression (Mermer et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25865495, 33004838, 35295842, 29895856, 28191889, 34653234, 34006619, 34028503)
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV003444213	SCV002102960	likely pathogenic	Epilepsy with myoclonic atonic seizures	2021-06-23	criteria provided, single submitter	clinical testing
OMIM	RCV003444213	SCV000224014	pathogenic	Epilepsy with myoclonic atonic seizures	2015-05-07	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001268638	SCV001931000	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001268638	SCV001952925	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV003444213	SCV002103321	not provided	Epilepsy with myoclonic atonic seizures		no assertion provided	phenotyping only	Variant reported in multiple GenomeConnect participants by multiple clinical testing laboratories. Variant classified by all laboratories as Pathogenic and reported most recently on 08-16-2019 by GeneDx and 12-12-2018 by UCLA Laboratory Genetics and Genomics. 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/.