Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000632640 | SCV000753825 | uncertain significance | Neurofibromatosis, type 2 | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 411 of the NF2 protein (p.Arg411His). 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: 527695). 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 with a negative predictive value of 80%. 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. |
Fulgent Genetics, |
RCV000765629 | SCV000896954 | uncertain significance | Familial meningioma; Neurofibromatosis, type 2; Schwannomatosis 1 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV001010465 | SCV001170667 | likely benign | Hereditary cancer-predisposing syndrome | 2023-05-19 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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. |
Centre for Mendelian Genomics, |
RCV001198705 | SCV001369700 | uncertain significance | Familial meningioma | 2019-12-05 | criteria provided, single submitter | clinical testing | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BS2. |
Broad Institute Rare Disease Group, |
RCV001249076 | SCV001423027 | uncertain significance | not specified | 2020-01-22 | criteria provided, single submitter | curation | The p.Arg411His variant in NF2 has not been previously reported in individuals with Neurofibromatosis but has been identified in 0.01181% (4/33872) of Latino chromosomes, 0.003403% (1/29382) of South Asian chromosomes, and 0.0009079% (1/110142) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201214090). This variant has also been reported as a VUS in ClinVar (Variation ID: 527695). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Arg411Cys, has been reported as a VUS in association with disease in ClinVar (Variation ID: 567682). In summary, while the clinical significance of the p.Arg411His variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1 (Richards 2015). |
Genome- |
RCV000632640 | SCV002044881 | uncertain significance | Neurofibromatosis, type 2 | 2021-11-07 | criteria provided, single submitter | clinical testing |