Submissions for variant NM_000268.4(NF2):c.1007G>A (p.Arg336Gln)

gnomAD frequency: 0.00001  dbSNP: rs587778554

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001063079	SCV001227913	uncertain significance	Neurofibromatosis, type 2	2023-10-22	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 336 of the NF2 protein (p.Arg336Gln). This variant is present in population databases (rs587778554, gnomAD 0.003%). 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: 134895). 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. 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.
Illumina Laboratory Services, Illumina	RCV001063079	SCV001310614	uncertain significance	Neurofibromatosis, type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508929	SCV001715369	uncertain significance	not provided	2021-03-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001063079	SCV002044868	uncertain significance	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426669	SCV002730915	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	The p.R336Q variant (also known as c.1007G>A), located in coding exon 11 of the NF2 gene, results from a G to A substitution at nucleotide position 1007. The arginine at codon 336 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well 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.
All of Us Research Program, National Institutes of Health	RCV001063079	SCV004822275	uncertain significance	Neurofibromatosis, type 2	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 336 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 been identified in 3/251398 chromosomes 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.
ITMI	RCV000121645	SCV000085843	not provided	not specified	2013-09-19	no assertion provided	reference population