Submissions for variant NM_001042492.3(NF1):c.3198-314G>A

dbSNP: rs2067116490

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204931	SCV001376162	pathogenic	Neurofibromatosis, type 1	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change falls in intron 24 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with neurofibromatosis type 1 (PMID: 21394830; internal data). ClinVar contains an entry for this variant (Variation ID: 936187). Studies have shown that this variant results in aberrant splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 21394830). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002249792	SCV002520146	likely pathogenic	not provided	2022-05-16	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing. In a minigene assay, this variant produced full-length transcript as well as two aberrant transcripts (Fernandez-Rodriguez 2011); No data available from control populations to assess the frequency of this variant; Also known as IVS19a-314G>A; This variant is associated with the following publications: (PMID: 21394830, 24506781, 32408052, 34273915)
Genome-Nilou Lab	RCV001204931	SCV002559937	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002322007	SCV002609691	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-03-04	criteria provided, single submitter	clinical testing	The c.3198-314G>A intronic likely pathogenic variant results from a G to A substitution 314 nucleotides before coding exon 25 in the NF1 gene. This alteration was first reported in an individual with a mild phenotype of neurofibromatosis type 1 (NF1) who was found to be mosaic for this alteration. In vitro functional studies found this alteration to affect splicing; however, the mutation was leaky and produced both truncated protein as well as normal protein (Fernandez-Rodriguez J et al. Hum Mutat. 2011;32(7):705-9). Using the BDGP and ESEfinder splice site prediction tools, this alteration creates an new alternate splice acceptor site that competes with the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genetics Department, Catlab	RCV001204931	SCV005419261	likely pathogenic	Neurofibromatosis, type 1	2024-08-28	criteria provided, single submitter	clinical testing	The c.3198-314G>A variant in the NF1 gene is absent from the gnomAD 4.1 database (PM2) and functional studies haven shown that the variant creates a criptic acceptor splicing site that creates 2 aberrant transcipts and a truncated protein (PMID: 21394830) (PS3). Moreover, the variant has been shown to segregate in a family (PP1). With all the available evidence, the variant is classified as likely pathogenic.