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

dbSNP: rs199474786

Total submissions: 10

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823359	SCV000964213	pathogenic	Neurofibromatosis, type 1	2024-05-24	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	2024-09-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21512413, 24676943, 24803665, 28152038, 18021924, 16527612, 31370276, 30308447, 9150739, 28924536, 29685074, 29415745, 12522551, 20605257, 31766501, 26659599, 25486365, 2121369, 37272364)
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
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000823359	SCV004805993	likely pathogenic	Neurofibromatosis, type 1	2024-03-25	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000823359	SCV005402217	likely pathogenic	Neurofibromatosis, type 1	2024-02-06	criteria provided, single submitter	clinical testing	The NF1 c.2693T>C (p.Leu898Pro) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but this prediction has not been confirmed by functional studies. This variant has been reported in multiple individuals with neurofibromatosis type 1 (PMID: 12522551, 20605257, 21512413, 24676943, internal data). In summary, this variant meets criteria to be classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000059178	SCV005413201	likely pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing	PP3, PP4, PM2_moderate, PM6
UniProtKB/Swiss-Prot	RCV000059178	SCV000090707	not provided	not provided		no assertion provided	not provided