Submissions for variant NM_001042492.3(NF1):c.2540T>C (p.Leu847Pro)

dbSNP: rs199474747

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205919	SCV000261269	pathogenic	Neurofibromatosis, type 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 847 of the NF1 protein (p.Leu847Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 10862084, 12552569, 15146469, 23668869, 24413922). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68323). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect NF1 function (PMID: 16513807). 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	2023-05-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34418705, 32980694, 24803665, 26432421, 12552569, 27838393, 16513807, 15146469, 27322474, 10712197, 16944272, 23668869, 10862084, 23758643, 29483232, 30530636, 32814709, 25486365, 2121369, 29926297, 29968256, 30014477, 29290338, 30308447, 31776437, 30287823, 31766501, 34694046, 35119474, 29559732, 24413922)
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
DASA	RCV000205919	SCV002061266	pathogenic	Neurofibromatosis, type 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.2540T>C;p.(Leu847Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 68323; PMID: 10712197; 12552569; 15146469; 23668869; 24413922; 10862084) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (hot-spot region) - PM1. This variant is not present in population databases (rs199474747, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 573019) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 24413922, 12552569) - PM6. Missense variant in NF1 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002054910	SCV002495860	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-06-15	criteria provided, single submitter	clinical testing	NF1 NM_000267.3 exon 21 p.Leu847Pro (c.2540T>C): This variant has been reported in the literature in numerous individuals with Neurofibromatosis type 1, segregating with disease in several affected family members (Fahsold 2000 PMID:10712197, McPherson 2015 PMID:26432421, Koczkowska 2018 PMID:29290338, Frayling 2019 PMID:30530636). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID:68323). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. Other variants at this position and nearby amino acids have been reported in association with disease; at least 1 publication cites exon 21 (in which this variant is located) as a mutational hotspot (Koczkowska 2018 PMID:29290338). In summary, this variant is classified as pathogenic based on the data above.
Suma Genomics	RCV000205919	SCV002543793	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000205919	SCV002561785	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453378	SCV002739341	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-10-21	criteria provided, single submitter	clinical testing	The p.L847P pathogenic mutation (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 occurs in a hotspot for missense mutations within NF1 and has been detected in multiple individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 (NF1) (Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Griffiths S et al. Fam Cancer, 2007;6:21-34; Ko JM et al. Pediatr Neurol, 2013 Jun;48:447-53; Nemethova M et al. Ann Hum Genet, 2013 Sep;77:364-79; Koczkowska M et al. Am. J. Hum. Genet., 2018 01;102:69-87; Tsipi M et al. J. Neurol. Sci., 2018 12;395:95-105). In a large cohort study, the variant was detected de novo in five individuals with NF1 and co-segregated with disease in five families (Koczkowska M et al. Am. J. Hum. Genet., 2018 01;102:69-87). This alteration was observed in with an allele frequency of 0 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003460651	SCV004199026	pathogenic	Juvenile myelomonocytic leukemia	2021-05-21	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	Atypical coarctation of aorta	2018-02-26	no assertion criteria provided	literature only
Laboratory for Genotyping Development, RIKEN	RCV003162464	SCV002758178	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000205919	SCV003840177	pathogenic	Neurofibromatosis, type 1		no assertion criteria provided	research