Submissions for variant NM_001042492.3(NF1):c.1139T>G (p.Leu380Arg)

dbSNP: rs1555611004

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812358	SCV001471572	uncertain significance	not provided	2020-07-14	criteria provided, single submitter	clinical testing	The NF1 c.1139T>G; p.Leu380Arg variant is reported in the literature in an individual affected with acute myeloid leukemia with a suspected diagnosis of neurofibromatosis type 1 (Weinberg 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 380 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Additionally, another amino acid substitution at this codon (p.Leu380Pro) has been reported in several probands with neurofibromatosis type 1 and segregated with disease in members of one family (Cunha 2016, Frayling 2019). However, given the lack of clinical and functional data, the significance of the p.Leu380Arg variant is uncertain at this time. References: Cunha KS et al. Hybridization Capture-Based Next-Generation Sequencing to Evaluate Coding Sequence and Deep Intronic Mutations in the NF1 Gene. Genes (Basel). 2016;7(12):133. Frayling IM et al. Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation. J Med Genet. 2019;56(4):209-219. Weinberg OK et al. Germline Predisposition to Hematolymphoid Neoplasia. Am J Clin Pathol. 2019;152(3):258-276.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001871672	SCV002147047	pathogenic	Neurofibromatosis, type 1	2022-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu380 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21520333, 27999334; Invitae). 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: 993576). This missense change has been observed in individual(s) with neurofibromatosis type 1 (Invitae). 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 380 of the NF1 protein (p.Leu380Arg).
Genome-Nilou Lab	RCV001871672	SCV002561870	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004548122	SCV004108232	uncertain significance	NF1-related disorder	2024-05-23	no assertion criteria provided	clinical testing	The NF1 c.1139T>G variant is predicted to result in the amino acid substitution p.Leu380Arg. This variant has been reported as a germline variant in an individual with acute myeloid leukemia and suspected diagnosis of neurofibromatosis (Weinberg et al. 2019. PubMed ID: 31309983). This variant has been reported de novo (aparently mosaic), along with a pathogenic variant in another gene, in an individual undergoing testing for Noonan spectrum disorders/rasopathies (Internal Data, PreventionGenetics). This variant has not been reported in a large population database, indicating this variant is rare. This variant has conflicting interpretations of pathogenicity in ClinVar of uncertain and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/993576/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.