Submissions for variant NM_001134407.3(GRIN2A):c.547T>A (p.Phe183Ile)

gnomAD frequency: 0.00004  dbSNP: rs587780353

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000117178	SCV000151342	likely benign	not specified	2013-05-14	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000711852	SCV000842258	uncertain significance	not provided	2017-09-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313887	SCV000847626	uncertain significance	Inborn genetic diseases	2017-10-27	criteria provided, single submitter	clinical testing	The p.F183I variant (also known as c.547T>A), located in coding exon 2 of the GRIN2A gene, results from a T to A substitution at nucleotide position 547. The phenylalanine at codon 183 is replaced by isoleucine, an amino acid with highly similar properties. In one study, this variant was detected in an individual with benign epilepsy with centrotemporal spikes (rolandic epilepsy). The variant was not present in the patient's asymptomatic father (mother's variant status unknown) (Lemke JR et al. Nat. Genet., 2013 Sep;45:1067-72). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000989528	SCV001011206	likely benign	Landau-Kleffner syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000989528	SCV001139948	benign	Landau-Kleffner syndrome	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000711852	SCV001815411	likely benign	not provided	2023-04-28	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Revvity Omics, Revvity	RCV000989528	SCV003815185	uncertain significance	Landau-Kleffner syndrome	2020-12-10	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000711852	SCV004026266	uncertain significance	not provided	2023-05-10	criteria provided, single submitter	clinical testing	PP3, PP4, PM2_SUP
CeGaT Center for Human Genetics Tuebingen	RCV000711852	SCV004141111	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000117178	SCV005394041	uncertain significance	not specified	2024-09-04	criteria provided, single submitter	clinical testing	Variant summary: GRIN2A c.547T>A (p.Phe183Ile) results in a non-conservative amino acid change located in the Receptor, ligand binding region domain (IPR001828) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250794 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GRIN2A causing Epilepsy, Focal, With Speech Disorder And With Or Without Mental Retardation, allowing no conclusion about variant significance. c.547T>A has been reported in the literature in individuals affected with clinical features of GRIN2A-related conditions (example, Bobboli_2018, Lemke_2013). These report(s) do not provide unequivocal conclusions about association of the variant with GRIN2A-related conditions. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (example, Serraz_2016). The following publications have been ascertained in the context of this evaluation (PMID: 29358611, 23933819, 27288002). ClinVar contains an entry for this variant (Variation ID: 129189). Based on the evidence outlined above, the variant was classified as uncertain significance.
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000656052	SCV000588328	pathogenic	Childhood epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15
PreventionGenetics, part of Exact Sciences	RCV004739405	SCV005351827	likely benign	GRIN2A-related disorder	2024-06-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).