ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1646T>C (p.Leu549Pro) (rs199474758)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000059155 SCV000808260 likely pathogenic not provided 2018-07-10 criteria provided, single submitter clinical testing The L549P missense variant in the NF1 gene has been reported previously in association with NF1 (Fahsold et al., 2000; Xu et al., 2014). It is not observed in large population cohorts (Lek et al., 2016). The L549P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The L549P variant is located within the GTPase activating domain (Luo et al., 2014). Missense variants in nearby residues (L550P, H553R/P) have been reported in the Human Gene Mutation Database in association with NF1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, a variant in the same codon (L549R) has been observed at GeneDx in an affected individual. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000632472 SCV000753657 pathogenic Neurofibromatosis, type 1 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 549 of the NF1 protein (p.Leu549Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with neurofibromatosis type 1 (NF1) in the Leiden Open-source Variation Database (PMID: 21520333). This variant has also been observed to segregate with NF1 in a family (Invitae), and has been reported in individuals affected with NF1 (PMID: 10712197, Invitae). ClinVar contains an entry for this variant (Variation ID: 68303). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot RCV000059155 SCV000090684 not provided not provided no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.