Submissions for variant NM_001042492.3(NF1):c.496_497del (p.Val166fs)

dbSNP: rs1135402788

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000497069	SCV000753484	pathogenic	Neurofibromatosis, type 1	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val166Leufs*7) 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 premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10726756, 18041031). ClinVar contains an entry for this variant (Variation ID: 431562). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000497069	SCV000807994	pathogenic	Neurofibromatosis, type 1	2018-06-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000497069	SCV002561579	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002285342	SCV002575292	pathogenic	not provided	2022-09-21	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10726756, 18041031, 32554297, 32980694, 23913538, 30287823)
Ambry Genetics	RCV002341170	SCV002643949	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-08-24	criteria provided, single submitter	clinical testing	The c.496_497delGT pathogenic mutation, located in coding exon 5 of the NF1 gene, results from a deletion of two nucleotides at nucleotide positions 496 to 497, causing a translational frameshift with a predicted alternate stop codon (p.V166Lfs*7). This mutation was detected in multiple unrelated individuals with neurofibromatosis type 1 (Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Yoshida Y et al. J Dermatol, 2018 Mar;45:363-364; Shi L et al. Stem Cell Res, 2020 07;46:101842). 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.
Medical Genetics, University of Parma	RCV000497069	SCV000588695	pathogenic	Neurofibromatosis, type 1	2017-02-02	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003159605	SCV002758457	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000497069	SCV003840153	pathogenic	Neurofibromatosis, type 1		no assertion criteria provided	research