Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000198059 | SCV000253691 | pathogenic | Neurofibromatosis, type 1 | 2023-08-10 | criteria provided, single submitter | clinical testing | This sequence change affects codon 950 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.2850G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 21520333, 26740943, 31717729). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 215989). This variant has been observed in individual(s) with NF1-related conditions (Invitae). |
| Ambry Genetics | RCV004558444 | SCV005047627 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-08-18 | criteria provided, single submitter | clinical testing | The c.2850G>C variant (also known as p.Q950H), located in coding exon 21 of the NF1 gene, results from a G to C substitution at nucleotide position 2850. The amino acid change results in glutamine to histidine at codon 950, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor site (c.2850G>A) has been shown to have a similar impact on splicing in multiple individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 (NF1). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |