Submissions for variant NM_001042492.3(NF1):c.2325G>A (p.Glu775=)

dbSNP: rs1555613932

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002315841	SCV000674094	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-02-28	criteria provided, single submitter	clinical testing	The c.2325G>A variant (also known as p.E775E) is located in coding exon 19 of the NF1 gene. This variant results from a G to A substitution at nucleotide position 2325. This nucleotide substitution does not change the glutamic acid at codon 775. However, this change occurs in the last base pair of coding exon 19, which makes it likely to have some effect on normal mRNA splicing. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with neurofibromatosis Type 1 (Ambry internal data) and was identified in a cohort of 27 patients with an NF1 alteration that had either a personal or family history of malignant peripheral nerve sheath tumors (Knewitz DK et al. Sarcoma, 2021 Oct;2021:9386823). In addition, two alterations at the same nucleotide position (c.2325G>T and c.2325G>C) have been reported in individuals with clinical features of neurofibromatosis type 1 (NF1) (Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25; Evans DG et al. EBioMedicine, 2016 May;7:212-20). Another alteration impacting the same donor site (c.2325+3A>G) has been detected in individuals with clinical diagnoses or suspicion of NF1 (Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660012	SCV000781948	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000660012	SCV001406161	pathogenic	Neurofibromatosis, type 1	2022-10-13	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with neurofibromatosis type 1 (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 775 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. ClinVar contains an entry for this variant (Variation ID: 485955). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.2325G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18546366, 27322474). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 19 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000660012	SCV001479167	likely pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV005001084	SCV005626865	pathogenic	not provided	2024-07-09	criteria provided, single submitter	clinical testing	Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, which functional studies support (Douben H et al. (2023) Hindawi Human Mutation. 2023 (Article ID 9628049):1-14); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 34646065); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34646065, Douben2023[Functional study], 27322474)