Submissions for variant NM_001042492.3(NF1):c.3315-2A>C

dbSNP: rs1555614914

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174610	SCV001337809	likely pathogenic	RASopathy	2020-01-13	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.3315-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: five predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251110 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3315-2A>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002451354	SCV002611447	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2017-06-22	criteria provided, single submitter	clinical testing	The c.3315-2A>C intronic pathogenic mutation results from a A to C substitution two nucleotides upstream from coding exon 26 of the NF1 gene. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998676	SCV005624681	likely pathogenic	not provided	2024-04-17	criteria provided, single submitter	clinical testing	The NF1 c.3315-2A>C variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal NF1 mRNA splicing. This variant has not been reported in individuals with NF1-related conditions in the published literature. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005093745	SCV005843124	pathogenic	Neurofibromatosis, type 1	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 25 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 23913538; internal data). ClinVar contains an entry for this variant (Variation ID: 917573). Studies have shown that disruption of this splice site results in multiple mRNA products, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.