Submissions for variant NM_001042492.3(NF1):c.1527+5G>A

dbSNP: rs1060500352

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460682	SCV000542165	pathogenic	Neurofibromatosis, type 1	2024-10-09	criteria provided, single submitter	clinical testing	This sequence change falls in intron 13 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 17311297; internal data). ClinVar contains an entry for this variant (Variation ID: 404566). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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	RCV000460682	SCV000781912	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000460682	SCV001479090	likely pathogenic	Neurofibromatosis, type 1	2024-08-15	criteria provided, single submitter	clinical testing	This missense variant is located at the +5 splice site of exon 13. In silico prediction programs predict that this variant may affect splicing. However, this prediction has not been confirmed by RNA functional studies. It has been reported previously in individuals with Neurofibromatosis type 1 (PMIDs: 17311297, 31766501). This variant has not been observed in population controls of the Genome Aggregation Database (gnomAD). Based on the evidence above, this variant is classified as likely pathogenic (ACMG criteria - PS4_Moderate, PM2, PP4, PP3, PP5).
GeneDx	RCV001753864	SCV002007399	likely pathogenic	not provided	2021-07-21	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31766501, 17311297)
Ambry Genetics	RCV002393082	SCV002705166	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-01-27	criteria provided, single submitter	clinical testing	The c.1527+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 13 in the NF1 gene. This nucleotide position is highly conserved in available vertebrate species. This variant was detected in multiple individuals with features of or clinical diagnosis of neurofibromatosis type 1 (Melloni G et al. Cancers (Basel), 2019 11;11:; personal communication with GeneDx, Invitae, and the Hospital for Sick Children). In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
NHS Central & South Genomic Laboratory Hub	RCV000460682	SCV005393931	pathogenic	Neurofibromatosis, type 1	2024-11-11	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV005222949	SCV005871508	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PS4_Supporting+PP4