Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000476470 | SCV000542127 | pathogenic | Neurofibromatosis, type 1 | 2024-10-15 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 1902 of the NF1 protein (p.Thr1902Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 25074460; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 404539). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV004559067 | SCV005048373 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-10-30 | criteria provided, single submitter | clinical testing | The p.T1902R variant (also known as c.5705C>G), located in coding exon 38 of the NF1 gene, results from a C to G substitution at nucleotide position 5705. The threonine at codon 1902 is replaced by arginine, an amino acid with similar properties. This variant has been observed in individual(s) with a personal and/or family history that is consistent with NF1-related disease (Pasmant E et al. Eur J Hum Genet, 2015 May;23:596-601, Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Center for Human Genetics, |
RCV000476470 | SCV000782061 | uncertain significance | Neurofibromatosis, type 1 | 2016-11-01 | flagged submission | clinical testing |