ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.1446G>A (p.Pro482=)

gnomAD frequency: 0.00001  dbSNP: rs753751373
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460735 SCV000553684 uncertain significance Neurofibromatosis, type 2 2024-01-04 criteria provided, single submitter clinical testing This sequence change affects codon 482 of the NF2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF2 protein. This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 412215). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 RCV002393165 SCV002697921 likely benign Hereditary cancer-predisposing syndrome 2020-02-06 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Baylor Genetics RCV003470520 SCV004191313 uncertain significance Familial meningioma 2023-04-21 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000460735 SCV004821917 uncertain significance Neurofibromatosis, type 2 2023-11-02 criteria provided, single submitter clinical testing This variant causes a G>A nucleotide substitution at the last conserved G nucleotide of exon 13 in the NF2 gene. This single nucleotide substitution does not change the coding sequence, however, splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. To our knowledge, RNA and functional studies have not been reported for this variant. This variant has been reported in an individual affected with sporadic meningioma (PMID: 15609345). This variant has not been identified 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.
Breakthrough Genomics, Breakthrough Genomics RCV004691779 SCV005195365 uncertain significance not provided criteria provided, single submitter not provided

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