Submissions for variant NM_001042492.3(NF1):c.2409+1G>C

dbSNP: rs1555614022

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002317197	SCV000670452	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2016-05-14	criteria provided, single submitter	clinical testing	The c.2409+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 20 of the NF1 gene. This alteration was reported in a cohort of individuals with pheochromocytoma and a clinical diagnosis of NF1 in an individual with multiple neurofibromas and cafe-au-lait spots (Bausch B, J. Clin. Endocrinol. Metab. 2007 Jul; 92(7):2784-92). In addition, this alteration was considered to be disruptive to splicing based on computational algorithms to predict splicing effects (Xiong HY, Science 2015 Jan; 347(6218):1254806). In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site 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).
Invitae	RCV000632426	SCV000753606	pathogenic	Neurofibromatosis, type 1	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 20 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 and pheochromocytoma (PMID: 17426081, 21520333). ClinVar contains an entry for this variant (Variation ID: 484037). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000632426	SCV000781951	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000632426	SCV001479242	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000632426	SCV002561762	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing