Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001059647 | SCV001224276 | uncertain significance | Neurofibromatosis, type 2 | 2023-03-01 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 534 of the NF2 protein (p.His534Tyr). This variant is present in population databases (rs769370159, gnomAD 0.003%). 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: 854568). 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. RNA analysis performed to evaluate the impact of this missense change 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. |
| All of Us Research Program, |
RCV001059647 | SCV004843789 | uncertain significance | Neurofibromatosis, type 2 | 2023-11-20 | criteria provided, single submitter | clinical testing | This missense variant replaces histidine with tyrosine at codon 534 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with a vestibular schwannoma (PMID: 23354516, 23921927), this individual also carried a pathogenic somatic variant in the NF2 gene. This variant has been identified in 1/251430 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. |
| Ambry Genetics | RCV004031891 | SCV005034265 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-11 | criteria provided, single submitter | clinical testing | The p.H534Y variant (also known as c.1600C>T), located in coding exon 15 of the NF2 gene, results from a C to T substitution at nucleotide position 1600. The histidine at codon 534 is replaced by tyrosine, an amino acid with similar properties. 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. |
| Baylor Genetics | RCV004570241 | SCV005052382 | uncertain significance | Familial meningioma | 2023-11-17 | criteria provided, single submitter | clinical testing |