Submissions for variant NM_000834.5(GRIN2B):c.1125G>A (p.Arg375=)

gnomAD frequency: 0.00003  dbSNP: rs200126922

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000237026	SCV000292570	likely benign	not provided	2020-01-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001364200	SCV001560335	uncertain significance	Intellectual disability, autosomal dominant 6; Developmental and epileptic encephalopathy, 27	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change affects codon 375 of the GRIN2B mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GRIN2B protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs200126922, gnomAD 0.01%). 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: 245615). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
PreventionGenetics, part of Exact Sciences	RCV004532975	SCV004120622	uncertain significance	GRIN2B-related disorder	2023-04-20	criteria provided, single submitter	clinical testing	The GRIN2B c.1125G>A variant is not predicted to result in an amino acid change (p.=). This is a synonymous change, but is located at the last base of the exon, and in silico splicing prediction tools indicate that it may diminish the canonical splice donor signal at this exon-intron boundary (Alamut Visual v1.6.1). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-13828679-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.