Submissions for variant NM_001042492.3(NF1):c.4465A>G (p.Ser1489Gly)

dbSNP: rs199474743

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000525910	SCV000628595	pathogenic	Neurofibromatosis, type 1	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1468 of the NF1 protein (p.Ser1468Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type 1 (NF1) (PMID: 9003501, 15060124, 23913538, 25480383, 26056819, 27838393; Invitae). ClinVar contains an entry for this variant (Variation ID: 68351). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002316216	SCV000670485	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-09	criteria provided, single submitter	clinical testing	The c.4402A>G variant (also known as p.S1468G), located in coding exon 33 of the NF1 gene, results from an A to G substitution at nucleotide position 4402. The serine at codon 1468 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in multiple individuals and families with clinical diagnoses of neurofibromatosis type 1 (NF1) and/or NF1-like phenotypes (Okumura A et al. Brain Dev., 2015 Aug;37:677-89; Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8; Zhang J et al. Sci Rep, 2015 Jun;5:11291). Functional analysis of RNA showed this alteration creates an aberrant splice acceptor site, and introduces a stop codon at amino acid position 1457 that results in a truncated NF1 protein (p.F1457*) (Okumura A et al. Brain Dev., 2015 Aug;37:677-89). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000525910	SCV001479122	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000525910	SCV001571434	pathogenic	Neurofibromatosis, type 1	2021-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000059204	SCV001767295	pathogenic	not provided	2020-09-08	criteria provided, single submitter	clinical testing	Exonic splice variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Sabbagh 2013, Okumura 2015, Zhang 2015); Not observed in large population cohorts (Lek 2016); In silico analysis suggests this variant impacts gene splicing; This variant is associated with the following publications: (PMID: 30245780, 15060124, 23913538, 27838393, 9003501, 9668168, 26056819, 25480383)
3billion	RCV000525910	SCV002520994	pathogenic	Neurofibromatosis, type 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.55; 3Cnet: 0.92). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23913538, 25480383, 26056819, 27838393, 9003501). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000525910	SCV002560057	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000525910	SCV002567801	pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000525910	SCV004801941	pathogenic	Neurofibromatosis, type 1	2024-03-26	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059204	SCV000090733	not provided	not provided		no assertion provided	not provided
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000525910	SCV000853071	pathogenic	Neurofibromatosis, type 1	2018-11-16	no assertion criteria provided	clinical testing