Submissions for variant NM_000268.4(NF2):c.595G>A (p.Ala199Thr)

gnomAD frequency: 0.00001  dbSNP: rs1261707371

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000553734	SCV000628878	uncertain significance	Neurofibromatosis, type 2	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 199 of the NF2 protein (p.Ala199Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 457924). 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.
Ambry Genetics	RCV001024724	SCV001186794	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-15	criteria provided, single submitter	clinical testing	The p.A199T variant (also known as c.595G>A), located in coding exon 6 of the NF2 gene, results from a G to A substitution at nucleotide position 595. The alanine at codon 199 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000553734	SCV002044851	uncertain significance	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV003236809	SCV003935787	uncertain significance	not provided	2022-12-21	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; This variant is associated with the following publications: (PMID: 11756419, 16324214, 28852847)
CeGaT Center for Human Genetics Tuebingen	RCV003236809	SCV004154850	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	NF2: PM2
Baylor Genetics	RCV003459196	SCV004199049	uncertain significance	Familial meningioma	2023-08-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000553734	SCV004834057	uncertain significance	Neurofibromatosis, type 2	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 199 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 2/251176 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.