Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002369445 | SCV002662522 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-07-16 | criteria provided, single submitter | clinical testing | The c.6799C>T variant (also known as p.Q2267*), located in coding exon 45 of the NF1 gene, results from a C to T substitution at nucleotide position 6799. This changes the amino acid from a glutamine to a stop codon within coding exon 45. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, this alteration and another nonsense pathogenic mutation (c.6792C>A) occur in cis in the same exon segregated in a large family with NF1. And RNA studies have demonstrated that individuals with double mutations (c.6792C>A and 6799C>T) resulted in higher abnormal splicing leading to skipping of exon 45 (Hernández-Imaz E et al. Clin Genet, 2013 May;83:462-6). This alteration has also been reported in an individual with a clinical diagnosis of NF1 (Pasmant E et al. Eur J Hum Genet, 2015 May;23:596-601). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive and direct evidence is insufficient at this time (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Baylor Genetics | RCV003471356 | SCV004190749 | likely pathogenic | Juvenile myelomonocytic leukemia | 2023-04-13 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003495289 | SCV004296798 | pathogenic | Neurofibromatosis, type 1 | 2023-12-26 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln2267*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1755477). 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. |