Submissions for variant NM_001042492.3(NF1):c.7078T>G (p.Phe2360Val)

dbSNP: rs2069866148

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001218243	SCV001390117	uncertain significance	Neurofibromatosis, type 1	2024-04-15	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2339 of the NF1 protein (p.Phe2339Val). 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: 947220). 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 not expected to disrupt NF1 protein function with a negative 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.
Genetic Services Laboratory, University of Chicago	RCV001819906	SCV002068136	uncertain significance	not specified	2020-05-27	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.7015T>G, in exon 47 that results in an amino acid change, p.Phe2339Val. This sequence change does not appear to have been previously described in patients with NF1-related disorders and has also not been described in population databases. The p.Phe2339Val change affects a moderately conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. In silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Phe2339Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Phe2339Val change remains unknown at this time.
Genome-Nilou Lab	RCV001218243	SCV002561033	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV003127694	SCV003803491	uncertain significance	not provided	2022-08-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25486365)
Ambry Genetics	RCV003163676	SCV003861652	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-01-07	criteria provided, single submitter	clinical testing	The p.F2339V variant (also known as c.7015T>G), located in coding exon 47 of the NF1 gene, results from a T to G substitution at nucleotide position 7015. The phenylalanine at codon 2339 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.