Submissions for variant NM_001042492.3(NF1):c.269T>G (p.Leu90Arg)

dbSNP: rs1555605393

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659961	SCV000781869	uncertain significance	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000659961	SCV002505607	likely pathogenic	Neurofibromatosis, type 1	2022-04-11	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM5_STR, PS4_SUP, PM2_SUP, PP2, PP3
Athena Diagnostics	RCV002473098	SCV002771581	uncertain significance	not provided	2021-10-22	criteria provided, single submitter	clinical testing
GeneDx	RCV002473098	SCV003761650	uncertain significance	not provided	2022-07-29	criteria provided, single submitter	clinical testing	Observed in individuals with suspected neurofibromatosis type 1 in published literature (Bianchessi et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32575496)
Ambry Genetics	RCV004559336	SCV005047604	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-05-12	criteria provided, single submitter	clinical testing	The p.L90R variant (also known as c.269T>G), located in coding exon 3 of the NF1 gene, results from a T to G substitution at nucleotide position 269. The leucine at codon 90 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in a cohort of patients, who were referred for suspected Neurofibromatosis Type 1 (NF1) (Bianchessi D et al. Genes (Basel), 2020 Jun;11:671). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000659961	SCV005702877	uncertain significance	Neurofibromatosis, type 1	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 90 of the NF1 protein (p.Leu90Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 547566). 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%. This variant disrupts the p.Leu90 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17426081, 30046999). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.