Submissions for variant NM_001042492.3(NF1):c.2329T>A (p.Trp777Arg)

dbSNP: rs876658853

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219741	SCV000274636	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-03-16	criteria provided, single submitter	clinical testing	Thep.W777Rvariant (also known as c.2329T>A), located in coding exon 20 of theNF1gene, results from a T to A substitution at nucleotide position 2329. The tryptophan at codon 777 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in two families with clinical neurofibromatosis type 1 (NF1) and segregated with disease in the only family tested (Cai Y et al, J. Dermatol. Sci. 2005 Aug; 39(2):125-7; Sabbagh A et al, Hum. Mutat. 2013 Nov; 34(11):1510-8). In addition, different amino acid substitutions at codon 777 (p.W777G and p.W777S) have been detected in multiple NF1 families to date (Fahsold R et al, Am. J. Hum. Genet. 2000 Mar; 66(3):790-818; Bendova S et al, J. Mol. Neurosci. 2007; 31(3):273-9; van Minkelen R et al, Clin. Genet. 2014 Apr; 85(4):318-27). 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 0.003% (greater than 30000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFTin silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000414491	SCV000491436	likely pathogenic	not provided	2020-11-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31766501, 22034633, 16005615, 27322474, 23656349, 23913538, 17726231, 10712197, 25486365, 26582918)
Invitae	RCV000541442	SCV000628433	pathogenic	Neurofibromatosis, type 1	2023-08-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 230937). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 27322474, 34589056). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 777 of the NF1 protein (p.Trp777Arg).
Genome-Nilou Lab	RCV000541442	SCV002561751	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444867	SCV002732941	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-05-17	criteria provided, single submitter	clinical testing	The p.W777R variant (also known as c.2329T>A), located in coding exon 20 of the NF1 gene, results from a T to A substitution at nucleotide position 2329. The tryptophan at codon 777 is replaced by arginine, an amino acid with dissimilar properties.The c.2329T>A and c.2329T>C alterations, both of which result in p.W777R, have been identified in several individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Cai Y et al. J. Dermatol. Sci. 2005 Aug; 39(2):125-7; Sabbagh A et al. Hum. Mutat. 2013 Nov; 34(11):1510-8; Evans DG et al. EBioMedicine, 2016 May;7:212-20, Ambry internal data). In addition, the c.2329T>A (p.W777R) alteration was determined to arise de novo in a patient with NF1; segregation studies showed both parents were negative for the alteration (Evans DG et al. EBioMedicine, 2016 May;7:212-20). Based on the available evidence, p.W777R is classified as a pathogenic mutation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000541442	SCV004814172	likely pathogenic	Neurofibromatosis, type 1	2024-04-16	criteria provided, single submitter	clinical testing
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000541442	SCV001482376	pathogenic	Neurofibromatosis, type 1	2019-05-31	no assertion criteria provided	research