Submissions for variant NM_001042492.3(NF1):c.655-1G>A

dbSNP: rs2143777263

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388612	SCV001589679	pathogenic	Neurofibromatosis, type 1	2022-10-11	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 7 (referred to as exon 5 in the literature) and introduces a premature termination codon (PMID: 8957181). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 1075101). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 8957181). This sequence change affects an acceptor splice site in intron 6 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Ambry Genetics	RCV002368226	SCV002661284	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-10-08	criteria provided, single submitter	clinical testing	The c.655-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 7 of the NF1 gene. In one study, this mutation was detected in an individual meeting NIH diagnostic criteria for Neurofibromatosis type 1 (NF1) and was shown to result in exon skipping and premature protein truncation at the mRNA level (Horn D et al. Electrophoresis, 1996 Oct;17:1559-63). 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.
GeneDx	RCV004699363	SCV005202027	pathogenic	not provided	2023-12-24	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36061378, 8957181)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004699363	SCV005624628	pathogenic	not provided	2024-06-03	criteria provided, single submitter	clinical testing	The NF1 c.655-1G>A variant disrupts a canonical splice-acceptor site and interferes with normal NF1 mRNA splicing. This variant has been reported in the published literature in individuals with neurofibromatosis type 1 (NF1) (PMIDs: 8957181 (1996), 16944272 (2007)) and NF1-associated dystrophic scoliosis (PMID: 36061378 (2022)). Analysis of mRNA shows the variant results in exon 7 skipping (referred to as exon 5 in the literature), which leads to a frameshift and truncated protein (PMID: 8957181 (1996)). 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 pathogenic.