Submissions for variant NM_001042492.3(NF1):c.5991G>A (p.Trp1997Ter)

dbSNP: rs876660696

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215669	SCV000278330	pathogenic	Hereditary cancer-predisposing syndrome	2015-09-16	criteria provided, single submitter	clinical testing	The p.W1997* pathogenic mutation (also known as c.5991G>A), located in coding exon 40 of the NF1 gene, results from a G to A substitution at nucleotide position 5991. This changes the amino acid from a tryptophan to a stop codon within coding exon 40. This variant has been seen as somatic mutation in a tumor from one patient with neurofibromatosis with a germline NF1 microdeletion and one patient with a reportedly sporadic pheochromocytoma (Laycock-van Spyk S et al. Hum. Genomics 2011 Oct; 5(6):623-90; Thomas L et al. Eur. J. Hum. Genet. 2012 Apr; 20(4):411-9; Welander J et al.J. Clin. Endocrinol. Metab. 2014 Jul; 99(7):E1352-60; Stenman A et al. Endocr. Pathol. 2015 Mar; 26(1):9-14). In addition to the data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660089	SCV000782066	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763391	SCV000894105	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-03-04	criteria provided, single submitter	clinical testing
Invitae	RCV000660089	SCV001387032	pathogenic	Neurofibromatosis, type 1	2023-04-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 233869). This premature translational stop signal has been observed in individual(s) with clinical features of neurofibromatosis, type 1 (PMID: 30014477, 31370276). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1976*) 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). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001797071	SCV002038587	pathogenic	not provided	2021-12-07	criteria provided, single submitter	clinical testing	Nonsense 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 (Lek 2016); This variant is associated with the following publications: (PMID: 30014477, 22108604, 32486389, 22155606, 31370276, 31730495)
Genome-Nilou Lab	RCV000660089	SCV002560163	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000660089	SCV003840176	pathogenic	Neurofibromatosis, type 1		no assertion criteria provided	research