ClinVar Miner

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

dbSNP: rs1135402864
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Total submissions: 3
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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
Invitae 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.

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