Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000458151 | SCV000542133 | pathogenic | Neurofibromatosis, type 1 | 2024-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 583 of the NF1 protein (p.Lys583Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 9 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 16944272, 17726231, 18041031, 21354044, 27074763, 27322474, 31370276). ClinVar contains an entry for this variant (Variation ID: 68306). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF1 protein function with a negative predictive value of 95%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 16 (PMID: 18041031, 27322474; Invitae). This variant disrupts a region of the NF1 protein in which other variant(s) (p.Leu578Pro) have been determined to be pathogenic (PMID: 12746402, 16479075, 17426081, 23668869, 25211147). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Center for Human Genetics, |
RCV000458151 | SCV000781928 | pathogenic | Neurofibromatosis, type 1 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000059158 | SCV000885836 | likely pathogenic | not provided | 2017-08-23 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV001266321 | SCV001444494 | pathogenic | Inborn genetic diseases | 2019-09-10 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV000458151 | SCV001479228 | pathogenic | Neurofibromatosis, type 1 | 2020-10-26 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000059158 | SCV002102634 | pathogenic | not provided | 2023-09-05 | criteria provided, single submitter | clinical testing | RNA studies indicate this variant leads to the creation of a cryptic splice site and the loss of 27 base pairs (Brinckmann et al., 2007; Valero et al., 2011, Evans et al., 2016) within the critical GTPase activating protein domain (Luo et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22155606, 16944272, 24803665, 17726231, 28068329, 10712197, 18041031, 27322474, 27074763, 25541118, 21354044, 30308447, 31370276, 34418705, 34308104, 25486365) |
Genome- |
RCV000458151 | SCV002561704 | likely pathogenic | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
MGZ Medical Genetics Center | RCV000458151 | SCV002579887 | pathogenic | Neurofibromatosis, type 1 | 2022-05-02 | criteria provided, single submitter | clinical testing | |
Laboratory of Medical Genetics, |
RCV000458151 | SCV004013914 | pathogenic | Neurofibromatosis, type 1 | 2023-05-24 | criteria provided, single submitter | clinical testing | PS4, PM1, PM2, PM5, PP5 |
Institute of Medical Genetics and Applied Genomics, |
RCV000458151 | SCV004231810 | pathogenic | Neurofibromatosis, type 1 | 2024-01-17 | criteria provided, single submitter | clinical testing | |
Uni |
RCV000059158 | SCV000090687 | not provided | not provided | no assertion provided | not provided |