ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2339C>A (p.Thr780Lys) (rs199474746)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468694 SCV000542103 pathogenic Neurofibromatosis, type 1 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 780 of the NF1 protein (p.Thr780Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is present in population databases (rs199474746, ExAC 0.01%). This variant has been reported in multiple individuals with Neurofibromatosis type 1 (PMID: 1071297, 12552569, 11735023, 26478990, 16944272). In one individual, it was found to be de novo (PMID: 15146469). ClinVar contains an entry for this variant (Variation ID: 68316). 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"). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000564052 SCV000666815 likely pathogenic Hereditary cancer-predisposing syndrome 2017-03-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000059168 SCV000885845 pathogenic not provided 2017-12-12 criteria provided, single submitter clinical testing The NF1 c.2339C>A; p.Thr780Lys variant (rs199474746) has been reported in multiple unrelated individuals with NF1, and was found de novo in at least one individual (De Luca 2003, De Luca 2004, Esposito 2015, Fahsold 2000, Han 2001). Additionally, two other alterations at this codon (p.Thr780Arg, p.Thr780Pro) have been reported in individuals with NF1 (Griffiths 2007, Laycock-van Spyk 2011). The p.Thr780Lys variant is reported as pathogenic in ClinVar (Variation ID: 68316), and is observed in the general population at a low overall allele frequency of 0.0004% (1/246132 alleles) in the Genome Aggregation Database. The threonine at codon 780 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster, Align GVGD) predict this variant to be damaging to the protein. Taken together, the p.Thr780Lys variant is considered pathogenic. REFERENCES De Luca A et al. NF1 gene analysis based on DHPLC. Hum Mutat. 2003 Feb;21(2):171-2. De Luca A et al. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum Mutat. 2004 Jun;23(6):629. Esposito T et al. A novel diagnostic method to detect truncated neurofibromin in neurofibromatosis 1. J Neurochem. 2015 Dec;135(6):1123-8. Fahsold 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. Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. Han SS et al. Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 ( NF1) gene. Hum Genet. 2001 Nov;109(5):487-97. Laycock-van Spyk S et al. Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. Hum Genomics. 2011 Oct;5(6):623-90.
UniProtKB/Swiss-Prot RCV000059168 SCV000090697 not provided not provided no assertion provided not provided

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