Submissions for variant NM_001042492.3(NF1):c.1642-449A>G

dbSNP: rs863224655

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197971	SCV000254481	pathogenic	Neurofibromatosis, type 1	2024-07-19	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 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: 16479075, 23668869; Invitae). ClinVar contains an entry for this variant (Variation ID: 216394). Studies have shown that this variant results in activation of a cryptic splice site, leading to altered splicing and introduction of a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001770149	SCV002004619	pathogenic	not provided	2023-07-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: aberrant splicing, leading to an insertion and frameshift effect (Douben et al., 2022; Koczkowska et al., 2023); In silico analysis supports a deleterious effect on splicing; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 16479075, 23668869, 36251260, 37186028)
CeGaT Center for Human Genetics Tuebingen	RCV001770149	SCV002498265	likely pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	NF1: PM2, PP4:Moderate, PS4:Moderate, PP3
Ambry Genetics	RCV002399747	SCV002704585	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-11-21	criteria provided, single submitter	clinical testing	The c.1642-449A>G intronic variant results from an A to G substitution 449 nucleotides upstream from coding exon 15 in the NF1 gene. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with neurofibromatosis type 1 (NF1)(Ambry internal data). This variant has been detected in individuals meeting diagnostic criteria for NF1 and RNA studies reported to result in aberrant splicing (Jeong SY et al. J Korean Med Sci, 2006 Feb;21:107-12; Ko JM et al. Pediatr Neurol, 2013 Jun;48:447-53; Douben HCW et al. Hum Mutat, 2022 Dec;43:2130-2140; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000197971	SCV005627535	likely pathogenic	Neurofibromatosis, type 1	2024-12-13	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM2,PS3_MOD