Submissions for variant NM_001042492.3(NF1):c.4532T>G (p.Leu1511Arg)

dbSNP: rs1135402864

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Genetics, University of Parma	RCV000497171	SCV000588788	likely pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497171	SCV002290712	likely pathogenic	Neurofibromatosis, type 1	2021-12-01	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of neurofibromatosis type I (PMID: 28961165). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1490 of the NF1 protein (p.Leu1490Arg). ClinVar contains an entry for this variant (Variation ID: 431646). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu1490 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25541118, 26635368, 29914388, 31717729). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt NF1 protein function.
Ambry Genetics	RCV002329181	SCV002636923	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2018-01-31	criteria provided, single submitter	clinical testing	The p.L1490R variant (also known as c.4469T>G), located in coding exon 33 of the NF1 gene, results from a T to G substitution at nucleotide position 4469. The leucine at codon 1490 is replaced by arginine, an amino acid with dissimilar properties. In one study, this alteration was reportedly de novo in an individual with a clinical diagnosis of Neurofibromatosis type 1 (NF1) (Bonatti F et al. Int J Mol Sci, 2017 Sep;18:). Two different alterations located at the same position, p.L1490P and p.L1490F, have been detected in individuals with diagnoses of NF1 (van Minkelen R et al. Clin. Genet., 2014 Apr;85:318-27; Duat Rodríguez A et al. An Pediatr (Barc), 2015 Sep;83:173-82). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.