ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.296A>G (p.Lys99Arg) (rs181794923)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000806495 SCV000946499 uncertain significance Neurofibromatosis, type 2 2020-09-23 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 99 of the NF2 protein (p.Lys99Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs181794923, ExAC 0.009%). This variant has not been reported in the literature in individuals with NF2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV001017700 SCV001178822 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing The p.K99R variant (also known as c.296A>G), located in coding exon 3 of the NF2 gene, results from an A to G substitution at nucleotide position 296. The lysine at codon 99 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in a cohort of Neurofibromatosis Type 2 (NF2) patients (Heineman TE et al. Otol. Neurotol. 2015 Jun;36:908-14). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.