Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001052619 | SCV001216839 | pathogenic | Neurofibromatosis, type 2 | 2023-04-23 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 848788). Disruption of this splice site has been observed in individuals with neurofibromatosis type 2 (PMID: 7913580, 8379998). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the NF2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF2 are known to be pathogenic (PMID: 9643284, 16983642). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002451214 | SCV002736081 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-03 | criteria provided, single submitter | clinical testing | The c.240+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 2 of the NF2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been reported in individuals with clincal diagnoses or features of neurofibromatosis type 2 (MacCollin M et al. Am J Hum Genet, 1994 Aug;55:314-20; Wallace AJ et al. Genet Test, 2004;8:368-80). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |