Submissions for variant NM_001042492.3(NF1):c.1393-2A>G

dbSNP: rs1555612266

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000582848	SCV000781906	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000582848	SCV001586972	pathogenic	Neurofibromatosis, type 1	2022-09-03	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individuals with clinical features of neurofibromatosis type 1 (Invitae). 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. ClinVar contains an entry for this variant (Variation ID: 492877). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 12 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).
GeneDx	RCV001764712	SCV002008680	pathogenic	not provided	2021-05-25	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of exon 13; Deletions involving coding exons of this gene are a known mechanism of disease (Stenson et al., 2014); Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016)
Genome-Nilou Lab	RCV000582848	SCV002561662	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002395504	SCV002696152	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-12-08	criteria provided, single submitter	clinical testing	The c.1393-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 13 in the NF1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is likely critical for protein function (Ambry internal data). This mutation was detected in an individual who met NIH diagnostic criteria for Neurofibromatosis type 1 (NF1) (Ambry Internal Data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000582848	SCV000692342	pathogenic	Neurofibromatosis, type 1	2014-10-06	no assertion criteria provided	clinical testing