Submissions for variant NM_001042492.3(NF1):c.2288T>G (p.Leu763Arg)

dbSNP: rs199474762

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196515	SCV000254486	pathogenic	Neurofibromatosis, type 1	2020-01-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu763 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10712197, 16005615, 21354044, 21520333). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual(s) with clinical features of neurofibromatosis type 1 (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 216396). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 763 of the NF1 protein (p.Leu763Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine.
Ambry Genetics	RCV000222376	SCV000274651	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-03-27	criteria provided, single submitter	clinical testing	The p.L763R variant (also known as c.2288T>G), located in coding exon 19 of the NF1 gene, results from a T to G substitution at nucleotide position 2288. The leucine at codon 763 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported as a disease-causing mutation, presumably being detected in a patient with neurofibromatosis type 1 (NF1)(Luijten M et al. J Med Genet. 2001 Jul;38(7):481-5). Adisease-causing mutation, p.L763P, hasbeen described in the same codon (Fahsold R et al. Am J Hum Genet. 2000 Mar;66(3):790-818).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 30000alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000196515	SCV000781944	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000196515	SCV002561739	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing