Submissions for variant NM_001042492.3(NF1):c.3496+1G>A

dbSNP: rs2067138719

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001864288	SCV002119976	pathogenic	Neurofibromatosis, type 1	2021-06-28	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 26 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). This variant is not present in population databases (ExAC no frequency). 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, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 31370276, 10712197, 9544853).
GeneDx	RCV002280193	SCV002568678	pathogenic	not provided	2022-08-29	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele, confirmed via RT-PCR and a minigene assay, in a gene for which loss-of-function is a known mechanism of disease (Giugliano et al., 2019; Morbidoni et al., 2021); Not observed in large population cohorts (gnomAD); Also known as IVS20+1G>A; This variant is associated with the following publications: (PMID: 17311297, 31370276, 31766501, 33673681)
Ambry Genetics	RCV003164101	SCV003893697	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-11-18	criteria provided, single submitter	clinical testing	The c.3496+1G>A intronic variant results from a G to A substitution one nucleotide(s) after coding exon 26 of the NF1 gene. RNA studies have demonstrated that this alteration results in skipping of exon 26 (Wimmer K et al. Hum Mutat, 2007 Jun;28:599-612). This alteration was identified in an individual with clinical features of neurofibromatosis type 1 (NF1) (Giugliano T et al. Genes (Basel), 2019 07;10:). Another alteration impacting the same donor site (c3496G>A) has been detected in individuals with a clinical diagnosis of NF1 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 likely pathogenic.