Submissions for variant NM_001042492.3(NF1):c.4231C>G (p.Leu1411Val)

dbSNP: rs199474789

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660051	SCV000782011	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000660051	SCV001234754	pathogenic	Neurofibromatosis, type 1	2023-07-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu1390 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19845691). 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. ClinVar contains an entry for this variant (Variation ID: 547642). This missense change has been observed in individual(s) with clinical features consistent with NF1-Noonan syndrome (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1390 of the NF1 protein (p.Leu1390Val).
Genome-Nilou Lab	RCV000660051	SCV002560028	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002331294	SCV002630428	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2018-09-19	criteria provided, single submitter	clinical testing	The p.L1390V variant (also known as c.4168C>G), located in coding exon 31 of the NF1 gene, results from a C to G substitution at nucleotide position 4168. The leucine at codon 1390 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. A different variant at the same position, p.L1390F, has been reported in one family with Neurofibromatosis-Noonan syndrome (NFNS) and segregated with disease in seven affected family members (Nyström AM et al. Clin. Genet. 2009 Dec; 76(6):524-34). This alteration is located in the RasGAP domain and is anticipated to disrupt protein function (Ambry internal data; Brownbridge GG et al. J. Biol. Chem., 1993 May;268:10914-9; Abel AM et al. Mol. Immunol., 2015 Jun;65:336-49). 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.