Submissions for variant NM_001042492.3(NF1):c.872A>C (p.Glu291Ala)

dbSNP: rs876660171

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223188	SCV000277376	uncertain significance	Hereditary cancer-predisposing syndrome	2015-07-21	criteria provided, single submitter	clinical testing	The p.E291A variant (also known as c.872A>C), located in coding exon 8 of the NF1 gene, results from an A to C substitution at nucleotide position 872. The glutamic acid at codon 291 is replaced by alanine, an amino acid with dissimilar 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 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. However, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence is limited at this time, the clinical significance of p.E291A remains unclear.
GeneDx	RCV000479894	SCV000570800	uncertain significance	not provided	2016-06-27	criteria provided, single submitter	clinical testing	This variant is denoted NF1 c.872A>C at the cDNA level, p.Glu291Ala (E291A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Glu291Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NF1 Glu291Ala occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether NF1 Glu291Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806878	SCV000946897	benign	Neurofibromatosis, type 1	2024-12-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000806878	SCV002561840	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558554	SCV005048684	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-09-29	criteria provided, single submitter	clinical testing	The c.872A>C (p.E291A) alteration is located in exon 8 (coding exon 8) of the NF1 gene. This alteration results from a A to C substitution at nucleotide position 872, causing the glutamic acid (E) at amino acid position 291 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect - Invitae Patient Insights Network	RCV001535488	SCV001749426	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 05-29-2020 by Invitae. 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.