Submissions for variant NM_000268.4(NF2):c.1547G>A (p.Arg516Gln)

dbSNP: rs1569309694

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000695910	SCV000824449	uncertain significance	Neurofibromatosis, type 2	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 516 of the NF2 protein (p.Arg516Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 574082). 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 not expected to disrupt NF2 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV001012056	SCV001172457	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-24	criteria provided, single submitter	clinical testing	The p.R516Q variant (also known as c.1547G>A), located in coding exon 14 of the NF2 gene, results from a G to A substitution at nucleotide position 1547. The arginine at codon 516 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000695910	SCV002044901	uncertain significance	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460942	SCV004199047	uncertain significance	Familial meningioma	2023-08-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000695910	SCV004840184	uncertain significance	Neurofibromatosis, type 2	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 516 of the NF2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with NF2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.