ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205919 SCV000261269 pathogenic Neurofibromatosis, type 1 2020-09-09 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 The p.L847P variant (also known as c.2540T>C), located in coding exon 21 of the NF1 gene, results from a T to C substitution at nucleotide position 2540. The leucine at codon 847 is replaced by proline, an amino acid with similar properties. This variant has been described in multiple cohorts of NF1 patients (<span style="background-color:initial">Fahsold R et al.Am. J. Hum. Genet. 2000 Mar; 66(3):790-818, Griffiths S et al. Fam. Cancer 2007; 6(1):21-34, Ko JM et al. Pediatr. Neurol. 2013 Jun; 48(6):447-53, Nemethova M et al. Ann. Hum. Genet. 2013 Sep; 77(5):364-79)<span style="background-color:initial">.<span style="background-color:initial">This variant was previously reported in the SNPDatabase as rs199474747 but<span style="background-color:initial">was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 55,000 alleles tested) in our clinical cohort.<span style="background-color:initial">This amino acid position is highly conserved on sequence alignment of available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.<span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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,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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000205919 SCV001361025 pathogenic Neurofibromatosis, type 1 2019-10-22 criteria provided, single submitter clinical testing Variant summary: NF1 c.2540T>C (p.Leu847Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250444 control chromosomes (gnomAD). c.2540T>C has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (Fahsold_2000, Koczkowska_2018). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submissions (evaluation after 2014) cite the variant four times as likely pathogenic and three times as pathogenic. In addition, another variant affecting the same codon, p.Leu847Arg, has been reported to associate with Neurofibromatosis 1 (via HGMD database). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000205919 SCV001478995 pathogenic Neurofibromatosis, type 1 2020-10-26 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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