Submissions for variant NM_001042492.3(NF1):c.2221T>A (p.Phe741Ile)

dbSNP: rs533819802

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572487	SCV000663088	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-15	criteria provided, single submitter	clinical testing	The p.F741I variant (also known as c.2221T>A), located in coding exon 18 of the NF1 gene, results from a T to A substitution at nucleotide position 2221. The phenylalanine at codon 741 is replaced by isoleucine, 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 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 110000alleles tested) in our clinical cohort.This amino acid position iswell conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this alterationremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858122	SCV002262242	uncertain significance	Neurofibromatosis, type 1	2023-03-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 480092). This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 741 of the NF1 protein (p.Phe741Ile). 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. 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. 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	RCV001858122	SCV002562010	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004559225	SCV005047598	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-03-27	criteria provided, single submitter	clinical testing	The c.2221T>A (p.F741I) alteration is located in exon 18 (coding exon 18) of the NF1 gene. This alteration results from a T to A substitution at nucleotide position 2221, causing the phenylalanine (F) at amino acid position 741 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.