Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001061549 | SCV001226294 | pathogenic | Neurofibromatosis, type 1 | 2023-02-03 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 9783703, 15060124, 15146469, 23758643, 30877234, 31370276). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change affects a donor splice site in intron 43 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). ClinVar contains an entry for this variant (Variation ID: 856149). 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. |
| Ambry Genetics | RCV002365739 | SCV002661639 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2016-08-10 | criteria provided, single submitter | clinical testing | The c.6641+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 43 of the NF1 gene. This alteration has been reported in a child with multiple café-au-lait macules and axillary and/or inguinal freckling (Nemethova M et al. Ann. Hum. Genet., 2013 Sep;77:364-79). 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 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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 likely pathogenic. |