Submissions for variant NM_000834.5(GRIN2B):c.3099C>G (p.Ser1033Arg)

gnomAD frequency: 0.00001  dbSNP: rs796052575

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187704	SCV000241301	uncertain significance	not provided	2014-04-01	criteria provided, single submitter	clinical testing	p.Ser1033Arg (AGC>AGG): c.3099 C>G in exon 13 of the GRIN2B gene (NM_000834.3). The S1033R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S1033R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Revvity Omics, Revvity	RCV000187704	SCV003817473	uncertain significance	not provided	2019-01-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765191	SCV004581575	uncertain significance	Intellectual disability, autosomal dominant 6; Developmental and epileptic encephalopathy, 27	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1033 of the GRIN2B protein (p.Ser1033Arg). This variant is present in population databases (rs796052575, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with GRIN2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 205717). 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 GRIN2B protein function. 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.