Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000132393 | SCV000187485 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2014-11-20 | criteria provided, single submitter | clinical testing | Thec.6919_6921delAAGvariant (also known as p.K2307del) is located in coding exon 46 of theNF1gene. This variant results from an in-frame deletion of 3 nucleotides betweenpositions 6919 to 6921, causing the removal of a well-conserved lysine residue at codon 2307. Additionally, this change removes the last three base pairs of coding exon 46 which makes it likely to have some effect on normal mRNA splicing.Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the nativesplice donor site; however, direct evidence is unavailable. This alteration was shown to co-segregate with individuals with a clinical diagnosis of NF1 in one family tested in our laboratory. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (>11,000 alleles tested) in our clinical cohort.Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV002514754 | SCV003321901 | pathogenic | Neurofibromatosis, type 1 | 2024-07-15 | criteria provided, single submitter | clinical testing | This variant, c.6856_6858del, results in the deletion of 1 amino acid(s) of the NF1 protein (p.Lys2286del), but otherwise preserves the integrity of the reading frame. This variant also falls at the last nucleotide of exon 45, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (Invitae). ClinVar contains an entry for this variant (Variation ID: 142920). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the NF1 protein in which other variant(s) (p.Lys2286Arg) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |