ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2693T>C (p.Leu898Pro)

dbSNP: rs199474786
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129792 SCV000184601 likely pathogenic Hereditary cancer-predisposing syndrome 2015-10-01 criteria provided, single submitter clinical testing The p.L898P variant (also known as c.2693T>C), located in coding exon 21 of the NF1 gene, results from a T to C substitution at nucleotide position 2693. The leucine at codon 898 is replaced by proline, an amino acid with similar properties. This alteration has been previously reported in the literature in individuals with sporadic neurofibromatosis type 1 and was described as a de novo mutation in one study (Wang Q et al. Hum. Genet. 2003; 112:117-23, Maynard J et al. Hum. Genet. 1997; 99:674-6). This variant was previously reported in the SNPDatabase as rs199474786; however, no frequency data is currently available from this database, the NHLBI Exome Sequencing Project (ESP), or the 1000 Genomes Project databases. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000823359 SCV000964213 pathogenic Neurofibromatosis, type 1 2023-11-09 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 898 of the NF1 protein (p.Leu898Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinically diagnosed neurofibromatosis type 1 (NF1) (PMID: 9150739, 12522551, 20605257, 21512413, 24676943, 29415745, 29685074). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68326). 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%. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000823359 SCV001479061 likely pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
GeneDx RCV000059178 SCV001822364 likely pathogenic not provided 2022-07-29 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: 21512413, 24676943, 24803665, 28152038, 18021924, 16527612, 31370276, 30308447, 9150739, 28924536, 29685074, 29415745, 12522551, 20605257, 31766501, 27535533, 25486365, 2121369, 26659599)
Genome-Nilou Lab RCV000823359 SCV002561797 likely pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002477208 SCV002798387 likely pathogenic Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2021-12-20 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000823359 SCV004805993 likely pathogenic Neurofibromatosis, type 1 2024-03-25 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059178 SCV000090707 not provided not provided no assertion provided not provided

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