ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2540T>C (p.Leu847Pro) (rs199474747)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205919 SCV000261269 pathogenic Neurofibromatosis, type 1 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 847 of the NF1 protein (p.Leu847Pro). The leucine residue is moderately 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 reported in several individuals affected with neurofibromatosis type 1 (PMID: 10712197, 12552569, 15146469, 23668869, 24413922, 10862084). In at least one of these individuals, the variant was not present in either parent (ie occurred de novo) (PMID: 24413922). ClinVar contains an entry for this variant (Variation ID: 68323). An experimental study using a model organism has shown that this missense variant does not have an effect on NF1 activity. However, the clinical significance of this finding is unclear at this time (PMID: 16513807). In summary, this variant is a rare missense change that is absent from the population and has been reported in several affected individuals. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000492608 SCV000581250 likely pathogenic Hereditary cancer-predisposing syndrome 2015-04-16 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507716 SCV000604490 likely pathogenic not specified 2016-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000059175 SCV000617578 pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing The L847P variant in the NF1 gene was observed in multiple individuals meeting diagnostic criteria for neurofibromatosis type 1, and was found to be apparently de novo in at least one individual (Fahsold et al., 2000; De Luca et al., 2003; Griffiths et al., 2007; Ben-Salem et al., 2014; McPherson et al., 2015; Cali et al., 2016; Evans et al., 2016; Koczkowska et al., 2018). The L847P variant was not observed in large population cohorts (Lek et al., 2016). It 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. In summary, we consider this variant to be pathogenic.
Center for Human Genetics, Inc RCV000205919 SCV000781954 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Medical Genomics Laboratory,Department of Genetics UAB RCV000205919 SCV000999173 pathogenic Neurofibromatosis, type 1 2019-06-05 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059175 SCV000090704 not provided not provided no assertion provided not provided
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000205919 SCV000925895 likely pathogenic Neurofibromatosis, type 1 2018-11-23 no assertion criteria provided clinical testing
Yale Center for Mendelian Genomics,Yale University RCV000845192 SCV000987128 likely pathogenic Midaortic syndrome 2018-02-26 no assertion criteria provided literature only

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