Submissions for variant NM_000268.4(NF2):c.1502T>C (p.Ile501Thr)

gnomAD frequency: 0.00001  dbSNP: rs767682136

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000632646	SCV000753831	uncertain significance	Neurofibromatosis, type 2	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 501 of the NF2 protein (p.Ile501Thr). This variant is present in population databases (rs767682136, gnomAD 0.009%). 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: 527701). 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	RCV001011925	SCV001172309	benign	Hereditary cancer-predisposing syndrome	2022-06-16	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome-Nilou Lab	RCV000632646	SCV002044898	uncertain significance	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV003126878	SCV003803138	uncertain significance	not provided	2022-08-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
All of Us Research Program, National Institutes of Health	RCV000632646	SCV004830017	uncertain significance	Neurofibromatosis, type 2	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 501 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 3/251496 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.