Submissions for variant NM_001042492.3(NF1):c.2158C>T (p.Arg720Trp)

dbSNP: rs759679443

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220091	SCV000276817	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-26	criteria provided, single submitter	clinical testing	The p.R720W variant (also known as c.2158C>T), located in coding exon 18 of the NF1 gene, results from a C to T substitution at nucleotide position 2158. The arginine at codon 720 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position.To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 110000 alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of p.R720W remains unclear.
Invitae	RCV000465439	SCV000542157	uncertain significance	Neurofibromatosis, type 1	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 720 of the NF1 protein (p.Arg720Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10336779). ClinVar contains an entry for this variant (Variation ID: 232635). 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 with a positive predictive value of 80%. 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.
GeneDx	RCV001775692	SCV002013570	uncertain significance	not provided	2019-05-07	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10336779)
Genome-Nilou Lab	RCV000465439	SCV002562003	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415909	SCV002724637	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-03-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002500735	SCV002777976	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-11-11	criteria provided, single submitter	clinical testing