Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001048346 | SCV001212346 | pathogenic | Neurofibromatosis, type 1 | 2023-09-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 845305). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 23913538, 30001348). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the NF1 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 NF1 are known to be pathogenic (PMID: 10712197, 23913538). |
| Ambry Genetics | RCV002339244 | SCV002638403 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2020-03-06 | criteria provided, single submitter | clinical testing | The c.480-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 5 of the NF1 gene. This mutation was detected in multiple individuals in a family diagnosed with neurofibromatosis type 1 (NF1) (Santoro C et al. PLoS ONE, 2018 Jul;13:e0200446). The mutation was detected in another individual suspected of having NF1 and was reported to result in inactivation of the native acceptor site, leading to exon skipping and use of a new acceptor site (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This splice prediction software predicts that this alteration will abolish the native splice acceptor site. Different variants affecting the same acceptor site (c.480-1G>T and c.480-2A>G) were also reported in individuals suspecting of having NF1 or fulfilling NF1 diagnostic criteria (Kluwe L et al. Hum. Mutat., 2002 Mar;19:309; Griffiths S et al. Fam. Cancer, 2007;6:21-34). In addition to the data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |
| Prevention |
RCV003393807 | SCV004119887 | pathogenic | NF1-related condition | 2023-05-01 | criteria provided, single submitter | clinical testing | The NF1 c.480-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Table S5 - Sabbagh et al 2013. PubMed ID: 23913538; Santoro et al. 2018. PubMed ID: 30001348). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. |