Submissions for variant NM_001042492.3(NF1):c.641dup (p.Asn214fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004560752	SCV005048629	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-07-06	criteria provided, single submitter	clinical testing	The c.641dupA pathogenic mutation, located in coding exon 6 of the NF1 gene, results from a duplication of A at nucleotide position 641, causing a translational frameshift with a predicted alternate stop codon (p.N214Kfs*2). This alteration was reported as a germline finding in a patient from a cohort of 47 individuals with Neurofibromatosis Type 1 (NF1) who underwent surgical sampling of a glioma (Lucas CG et al. Acta Neuropathol, 2022 Oct;144:747-765). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005100848	SCV005837504	pathogenic	Neurofibromatosis, type 1	2024-10-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn214Lysfs*2) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). 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. For these reasons, this variant has been classified as Pathogenic.