ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs181794923
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000806495 SCV000946499 uncertain significance Neurofibromatosis, type 2 2023-10-05 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 99 of the NF2 protein (p.Lys99Arg). This variant is present in population databases (rs181794923, 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: 651188). 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 RCV001017700 SCV001178822 benign Hereditary cancer-predisposing syndrome 2021-12-17 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 RCV000806495 SCV002044841 uncertain significance Neurofibromatosis, type 2 2021-11-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV001017700 SCV002528191 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-13 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV000806495 SCV004824784 uncertain significance Neurofibromatosis, type 2 2023-06-28 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 99 of the NF2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251468 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.

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