ClinVar Miner

Submissions for variant NM_003042.4(SLC6A1):c.1648G>A (p.Gly550Arg)

dbSNP: rs886042046
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000286162 SCV000330886 pathogenic not provided 2023-03-24 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect; p.(G550R) abolished GABA transport activity (Mattison et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27824329, 25363768, 28714951, 34011629, 31981491, 31785789, 31332282, 28191890, 30132828)
Mendelics RCV003444225 SCV001136320 likely pathogenic Myoclonic-astatic epilepsy 2019-05-28 criteria provided, single submitter clinical testing
Genomic Medicine Lab, University of California San Francisco RCV001007935 SCV001167646 likely pathogenic Global developmental delay 2018-11-29 criteria provided, single submitter clinical testing
Invitae RCV003595908 SCV001560690 uncertain significance Myoclonic-atonic epilepsy 2023-10-28 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 550 of the SLC6A1 protein (p.Gly550Arg). 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: 25363768, 27824329, 30132828, 31332282, 31981491; Invitae). ClinVar contains an entry for this variant (Variation ID: 280932). 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 95%. Experimental studies have shown that this missense change affects SLC6A1 function (PMID: 30132828, 34028503, 36674476). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV003444225 SCV004027812 likely pathogenic Myoclonic-astatic epilepsy 2023-06-27 criteria provided, single submitter clinical testing Criteria applied: PS1,PS4_MOD,PM2_SUP,PM5_SUP,PP3

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