Submissions for variant NM_001042492.3(NF1):c.2288T>C (p.Leu763Pro)

dbSNP: rs199474762

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165288	SCV000216006	pathogenic	Hereditary cancer-predisposing syndrome	2016-03-09	criteria provided, single submitter	clinical testing	The p.L763P pathogenic mutation (also known as c.2288T>C), located in coding exon 19 of the NF1 gene, results from a T to C substitution at nucleotide position 2288. The leucine at codon 763 is replaced by proline, an amino acid with similar properties. This mutation has been observed in multiple individuals meeting clinical NF1 diagnostic criteria, including an apparent de novo mutation in one affected individual with unaffected parents (Fahsold R, Am. J. Hum. Genet. 2000 Mar; 66(3):790-818; Valero MC, J Mol Diagn 2011 Mar; 13(2):113-22).<span style="background-color:initial">Based on protein sequence alignment, 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 available evidence, p.L763P is classified as a pathogenic mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220933	SCV000271252	likely pathogenic	Neurofibromatosis, type 1	2015-07-30	criteria provided, single submitter	clinical testing	The p.Leu763Pro variant in NF1 has been reported in 2 individuals with Neurofibr omatosis type 1, with an apparently de novo occurence in one of these individual s (Fahsold 2000, Valero 2011). This variant was absent from large population stu dies. Computational prediction tools and conservation analysis do not provide st rong support for or against an impact to the protein. In summary, although addit ional studies are required to fully establish its clinical significance, the p.L eu763Pro variant is likely pathogenic.
Invitae	RCV000220933	SCV000628428	pathogenic	Neurofibromatosis, type 1	2023-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 763 of the NF1 protein (p.Leu763Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 16005615, 21354044, 30530636, 31370276; Invitae). ClinVar contains an entry for this variant (Variation ID: 68312). 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. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001401	SCV001158609	likely pathogenic	not specified	2018-09-27	criteria provided, single submitter	clinical testing	The NF1 c.2288T>C; p.Leu763Pro variant (rs199474762) has been described in individuals affected with neurofibromatosis type 1, and segregating with disease in at least one family (Cai 2005, Fashold 2000, Valero 2011). It is reported as pathogenic/likely pathogenic in ClinVar (Variation ID: 68312) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 763 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered likely pathogenic. REFERENCES Cai Y et al. Two novel mutations of the NF1 gene in Chinese Han families with type 1 neurofibromatosis. J Dermatol Sci. 2005 Aug;39(2):125-7. Fashold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Valero M et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011 Mar;13(2):113-22.
CeGaT Center for Human Genetics Tuebingen	RCV000059164	SCV001247186	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000220933	SCV002561740	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000059164	SCV003845828	likely pathogenic	not provided	2022-09-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in multiple unrelated patients with a clinical diagnosis of neurofibromatosis type 1 (Fahsold et al., 2000; Frayling et al., 2019; Giugliano et al., 2019; Kang et al., 2020); This variant is associated with the following publications: (PMID: 24803665, 31370276, 25486365, 30530636, 32107864, 16005615, 21354044, 31776437, 10712197)
UniProtKB/Swiss-Prot	RCV000059164	SCV000090693	not provided	not provided		no assertion provided	not provided