Submissions for variant NM_001042492.3(NF1):c.6921+1G>A

dbSNP: rs1060500355

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000476980	SCV000542170	pathogenic	Neurofibromatosis, type 1	2023-08-06	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 10607834, 11735023, 11857752, 17426081). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 45 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). ClinVar contains an entry for this variant (Variation ID: 404571). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000476980	SCV001499693	pathogenic	Neurofibromatosis, type 1	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001558427	SCV001780371	pathogenic	not provided	2019-03-11	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24789688, 24232412, 17120035, 21520333, 11735023, 25525159)
Genome-Nilou Lab	RCV000476980	SCV002560221	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002374746	SCV002667583	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-03-20	criteria provided, single submitter	clinical testing	The c.6858+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 45 of the NF1 gene. This mutation was identified in an individual with a clinical diagnosis of neurofibromatosis type 1 (Han SS et al. Hum. Genet., 2001 Nov;109:487-97). Two disease-causing mutations, c.6858+1G>T and c.6858+1G>C, have been described at the same position (Kluwe L et al. Hum. Mutat., 2002 Mar;19:309; Wimmer K et al. Hum. Mutat., 2007 Jun;28:599-612). 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	RCV000476980	SCV000588827	likely pathogenic	Neurofibromatosis, type 1	2017-02-02	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000476980	SCV000692364	pathogenic	Neurofibromatosis, type 1	2016-12-13	no assertion criteria provided	clinical testing