Submissions for variant NM_001042492.3(NF1):c.6642+1G>T

dbSNP: rs1060500345

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000458814	SCV000542156	pathogenic	Neurofibromatosis, type 1	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 42 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 clinical features of neurofibromatosis type 1 (PMID: 16835897, 23913538; Invitae). ClinVar contains an entry for this variant (Variation ID: 404558). 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	RCV000458814	SCV000782076	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002356636	SCV001187613	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-06-01	criteria provided, single submitter	clinical testing	The c.6579+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 42 of the NF1 gene. This alteration was reported in two individuals with a clinical diagnosis of neurofibromatosis type 1 (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). In addition, this alteration was identified in a child under age 10 with at least six cafe-au-lait macules, freckling, and neurofibromas (Giugliano T et al. Genes (Basel), 2019 07;10). RNA data indicate that this variant affects the donor site and results in an out-of-frame transcript (Giugliano T et al. Genes (Basel), 2019 07;10; Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Medical Genetics, University of Parma	RCV000458814	SCV001218925	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000458814	SCV002560196	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing