Submissions for variant NM_001042492.3(NF1):c.4235G>C (p.Arg1412Thr)

dbSNP: rs1555618516

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626643	SCV000747345	likely pathogenic	Cafe au lait spots, multiple; Neurofibroma; Abnormality of vision	2017-01-01	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660052	SCV000782012	uncertain significance	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000660052	SCV000962246	pathogenic	Neurofibromatosis, type 1	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 1391 of the NF1 protein (p.Arg1391Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NF1- Noonan syndrome and neurofibormatosis type 1 (NF1) (PMID: 24789688, 27322474; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 523345). 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.Arg1391 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7581973, 9003501, 16513807, 22807134, 27322474). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002319052	SCV001183675	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-09-03	criteria provided, single submitter	clinical testing	The p.R1391T pathogenic mutation (also known as c.4172G>C), located in coding exon 31 of the NF1 gene, results from a G to C substitution at nucleotide position 4172. The arginine at codon 1391 is replaced by threonine, an amino acid with similar properties. This variant was reported in multiple individuals who met clinical criteria for Neurofibromatosis type1 or were suspected of having Neurofibromatosis type 1 (van Minkelen R et al. Clin Genet, 2014 Apr;85:318-27; Xu W et al. Int J Mol Med, 2014 Jul;34:53-60; Evans DG et al. EBioMedicine, 2016 May;7:212-20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Another variant at the same codon, p.R1391S (c.4173A>T), has been detected in individuals with Neurofibromatosis type 1 (Upadhyaya M et al. Hum. Genet., 1997 Jan;99:88-92; Evans DG et al. EBioMedicine, 2016 May;7:212-20). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000660052	SCV001479070	uncertain significance	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV004791637	SCV005413204	likely pathogenic	not provided	2024-03-19	criteria provided, single submitter	clinical testing	PP3, PP4, PM2_moderate, PS4_moderate