Submissions for variant NM_001042492.3(NF1):c.1748A>G (p.Lys583Arg)

dbSNP: rs199474760

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458151	SCV000542133	pathogenic	Neurofibromatosis, type 1	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 583 of the NF1 protein (p.Lys583Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 9 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 16944272, 17726231, 18041031, 21354044, 27074763, 27322474, 31370276). ClinVar contains an entry for this variant (Variation ID: 68306). 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 not expected to disrupt NF1 protein function with a negative predictive value of 95%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 16 (PMID: 18041031, 27322474; Invitae). This variant disrupts a region of the NF1 protein in which other variant(s) (p.Leu578Pro) have been determined to be pathogenic (PMID: 12746402, 16479075, 17426081, 23668869, 25211147). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000458151	SCV000781928	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000059158	SCV000885836	likely pathogenic	not provided	2017-08-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558296	SCV001444494	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-02-06	criteria provided, single submitter	clinical testing	The p.K583R pathogenic mutation (also known as c.1748A>G), located in coding exon 16 of the NF1 gene, results from an A to G substitution at nucleotide position 1748. The lysine at codon 583 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported de novo in an individual with features of neurofibromatosis type 1 (Tsipi M et al. J. Neurol. Sci., 2018 12;395:95-105). This variant has also been identified in multiple individuals meeting diagnostic criteria for NF1 and has been shown to result in abnormal splicing (Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818; Brinckmann A et al. Electrophoresis, 2007 Dec;28:4295-301; Bendova S et al. J. Mol. Neurosci., 2007;31:273-9; Evans DG et al. EBioMedicine, 2016 May;7:212-20). Based on the available evidence, this variant is classified as a pathogenic mutation.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000458151	SCV001479228	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000059158	SCV002102634	pathogenic	not provided	2023-09-05	criteria provided, single submitter	clinical testing	RNA studies indicate this variant leads to the creation of a cryptic splice site and the loss of 27 base pairs (Brinckmann et al., 2007; Valero et al., 2011, Evans et al., 2016) within the critical GTPase activating protein domain (Luo et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22155606, 16944272, 24803665, 17726231, 28068329, 10712197, 18041031, 27322474, 27074763, 25541118, 21354044, 30308447, 31370276, 34418705, 34308104, 25486365)
Genome-Nilou Lab	RCV000458151	SCV002561704	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000458151	SCV002579887	pathogenic	Neurofibromatosis, type 1	2022-05-02	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000458151	SCV004013914	pathogenic	Neurofibromatosis, type 1	2023-05-24	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PM5, PP5
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000458151	SCV004231810	pathogenic	Neurofibromatosis, type 1	2024-01-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000458151	SCV005368017	likely pathogenic	Neurofibromatosis, type 1	2024-03-18	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4_MOD,PM4,PM2_SUP
UniProtKB/Swiss-Prot	RCV000059158	SCV000090687	not provided	not provided		no assertion provided	not provided