Submissions for variant NM_001042492.3(NF1):c.4836-2A>C

dbSNP: rs1555533265

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523506	SCV000617585	pathogenic	not provided	2017-07-05	criteria provided, single submitter	clinical testing	This variant is denoted NF1 c.4773-2A>C or IVS35-2A>C and consists of an A>C nucleotidesubstitution at the -2 position of intron 35 of the NF1 gene. This variant destroys a canonical splice acceptor site and ispredicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least two individualswith a diagnosis or clinical suspicion of Neurofibromatosis Type 1 (Pros 2008, Zhang 2015), and was shown on RT-PCR analysis to result in an out-of-frame deletion within exon 36 (Zhang 2015). Based on the current evidence, weconsider this variant to be pathogenic
Ambry Genetics	RCV002341221	SCV002634719	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-05-13	criteria provided, single submitter	clinical testing	The c.4773-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 36 in the NF1 gene. This variant has been reported in individuals with neurofibromatosis type I (Ambry internal data; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Zhang J et al. Sci Rep, 2015 Jun;5:11291). RT-PCR and cDNA studies showed abnormal transcripts resulting from a deletion in exon 36 (Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Zhang J et al. Sci Rep, 2015 Jun;5:11291). 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.