ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.5426G>T (p.Arg1809Leu) (rs771529172)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492566 SCV000581336 likely pathogenic Hereditary cancer-predisposing syndrome 2016-07-07 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,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Fulgent Genetics,Fulgent Genetics RCV000762992 SCV000893437 pathogenic Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000190890 SCV000628661 pathogenic Neurofibromatosis, type 1 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 1809 of the NF1 protein (p.Arg1809Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with non-classic neurofibromatosis type 1 (NF1), who also had phenotypes overlapping with Noonan syndrome (PMID: 14569132, 16944272, 25966637, 26178382). This variant was reported to segregate with disease in multiple families (PMID: 25966637, 26178382). ClinVar contains an entry for this variant (Variation ID: 208854). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The arginine residue is located at the C-terminus of the alpha-helix in the pleckstrin homology (PH)-like domain, which likely interacts with either other domains of the NF1 protein (neurofibromin) or its ligands (PMID: 24357598). A different missense substitution at this codon (p.Arg1809Cys) has been determined to be pathogenic (PMID: 24789688, 24357598, 19120036, 12807981, 26178382), suggesting that the arginine residue is critical for NF1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Medical Genomics Laboratory,Department of Genetics UAB RCV000190890 SCV000245764 pathogenic Neurofibromatosis, type 1 no assertion criteria provided clinical testing

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