Submissions for variant NM_001042492.3(NF1):c.4394A>G (p.Asn1465Ser)

dbSNP: rs786202492

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165332	SCV000216055	uncertain significance	Hereditary cancer-predisposing syndrome	2014-08-20	criteria provided, single submitter	clinical testing	The p.N1465S variant (also known as c.4394A>G), located in coding exon 33 of the NF1 gene, results from an A to G substitution at nucleotide position 4394. The asparagine at codon 1465 is replaced by serine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with coverage at this position.<span style="background-color: initial;">To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 11000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this<span style="background-color: initial;">amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and deleterious by PolyPhen and SIFT <em style="background-color: initial;">in silico<span style="background-color: initial;"> analyses, respectively.<span style="background-color: initial;">Since supporting evidence is limited at this time, the clinical significance of p.N1465S remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000764111	SCV000895079	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001222970	SCV001395096	uncertain significance	Neurofibromatosis, type 1	2024-09-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1444 of the NF1 protein (p.Asn1444Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 185835). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001222970	SCV002560419	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558373	SCV005047793	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-05-11	criteria provided, single submitter	clinical testing	The c.4331A>G (p.N1444S) alteration is located in exon 32 (coding exon 32) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 4331, causing the asparagine (N) at amino acid position 1444 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect - Invitae Patient Insights Network	RCV003483537	SCV004228820	not provided	Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-09-2020 by Lab Invitae. This variant was reported as possibly mosaic in this individual. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.