Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002376015 | SCV002685902 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2020-12-21 | criteria provided, single submitter | clinical testing | The c.889-1delG intronic variant, located in intron 8 of the NF1 gene, results from a deletion of one nucleotide within intron 8 of the NF1 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 acceptor 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 missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data). Another alteration impacting the same acceptor site (c.889-2A>G) has been identified in multiple individuals and families with neurofibromatosis type 1 and has been shown via RT-PCR studies to cause aberrant splicing (Klose A et al. Am. J. Med. Genet., 1999 Mar;83:6-12; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Messiaen L et al. Hum. Mutat., 2011 Feb;32:213-9; Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60). c.889-1delG was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| 3billion | RCV003152798 | SCV003841679 | pathogenic | Neurofibromatosis-Noonan syndrome | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with NF1 related disorder (ClinVar ID: VCV001765006). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |