Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001236229 | SCV001408944 | uncertain significance | Neurofibromatosis, type 1 | 2022-08-09 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with NF1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 962380). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 2214 of the NF1 protein (p.Arg2214Ile). This variant also falls at the last nucleotide of exon 43, which is part of the consensus splice site for this exon. |
| Ambry Genetics | RCV002366046 | SCV002663233 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-11-07 | criteria provided, single submitter | clinical testing | The p.R2214I variant (also known as c.6641G>T), located in coding exon 43 of the NF1 gene, results from a G to T substitution at nucleotide position 6641. The amino acid change results in arginine to isoleucine at codon 2214, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 43, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is conserved through mammals. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |