ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.947T>G (p.Leu316Trp) (rs750633919)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000436646 SCV000520003 uncertain significance not provided 2021-02-12 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16983642, 16324214, 16532029, 11756419)
Invitae RCV000534581 SCV000628888 uncertain significance Neurofibromatosis, type 2 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with tryptophan at codon 316 of the NF2 protein (p.Leu316Trp). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and tryptophan. This variant is present in population databases (rs750633919, ExAC 0.02%). This variant has been reported in an individual affected with bilateral vestibular schwannomas (PMID: 16983642). ClinVar contains an entry for this variant (Variation ID: 380975). Experimental studies using a yeast two-hybrid screen have shown that this missense change does not affect the binding interaction between Merlin (the protein encoded by NF2) and HEI10 (a cell cycle regulator) (PMID: 16532029). 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 RCV000561700 SCV000674139 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The p.L316W variant (also known as c.947T>G), located in coding exon 10 of the NF2 gene, results from a T to G substitution at nucleotide position 947. The leucine at codon 316 is replaced by tryptophan, an amino acid with similar properties. This alteration was reported in an individual with bilateral vestibular schwannomas (Ahronowitz I et al. Hum. Mutat. 2007 Jan;28(1):1-12). A structural analysis of L316W demonstrated that this alteration is exposed to solvent regions and, therefore, is unlikely to impact molecular function (Shimizu T et al. J. Biol. Chem. 2002 Mar;277:10332-6). Another study indicated that this alteration did not affect merlin binding to HEI10 (Grönholm M et al. Oncogene 2006 Jul;25(32):4389-98). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics RCV000534581 SCV000839517 uncertain significance Neurofibromatosis, type 2 2018-07-02 criteria provided, single submitter clinical testing

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