Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000692867 | SCV000820713 | uncertain significance | Neurofibromatosis, type 1 | 2021-08-09 | criteria provided, single submitter | clinical testing | 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). Studies have shown that this variant results in skipping of exon 7 (also known as exon 5) and introduces a premature termination codon (PMID: 18546366). The resulting mRNA is expected to undergo nonsense-mediated decay. 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: 571661). This variant has been observed in individual(s) with clinical features of neurofibromatosis type I (PMID: 18546366; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 244 of the NF1 protein (p.Glu244Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. |
| Ce |
RCV001091252 | SCV001247179 | pathogenic | not provided | 2018-04-01 | criteria provided, single submitter | clinical testing | |
| Medical Genetics, |
RCV000692867 | SCV002567804 | pathogenic | Neurofibromatosis, type 1 | 2022-08-17 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001091252 | SCV004222180 | pathogenic | not provided | 2011-12-02 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individuals with neurofibromatosis 1 (NF1) (PMID: 18546366 (2008), 33999308 (2021)). Published splicing studies have shown that this variant results in aberrant NF1 splicing and causes truncated NF1 protein product (PMID: 18546366 (2018)). The variant has also been shown to result in reduced NF1 gene expression levels (PMID: 33999308 (2021)). Based on the available information, this variant is classified as likely pathogenic. |