Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165426 | SCV000216155 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-08-19 | criteria provided, single submitter | clinical testing | The c.3496+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 26 in the NF1 gene. 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. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position.<span style="background-color: initial;">To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 11000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this<span style="background-color: initial;">nucleotide position is highly conserved through mammals. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native donor splice site, and is predicted to weaken (but not abolish) the efficacy of the native donor splice site by ESEfinder; however, direct evidence is unavailable.<span style="background-color: initial;">Since supporting evidence is limited at this time, the clinical significance of c.3496+5G>C remains unclear. |
| Labcorp Genetics |
RCV002516480 | SCV003441797 | pathogenic | Neurofibromatosis, type 1 | 2022-03-26 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 26 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 26 and introduces a premature termination codon (PMID: 18546366; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 185921). This variant is also known as being located in intron 20. This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 17311297, 18546366; Invitae). This variant is not present in population databases (gnomAD no frequency). |
| Center for Genomic Medicine, |
RCV002516480 | SCV004806166 | uncertain significance | Neurofibromatosis, type 1 | 2024-03-25 | criteria provided, single submitter | clinical testing |