ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.6642+18A>G

dbSNP: rs1555534893
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000660095 SCV000782075 uncertain significance Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000660095 SCV000831872 likely pathogenic Neurofibromatosis, type 1 2024-01-09 criteria provided, single submitter clinical testing This sequence change falls in intron 42 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 disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 23913538; Invitae). ClinVar contains an entry for this variant (Variation ID: 547676). Studies have shown that this variant results in the retention of the first 17 nt of intron 42 and introduces a premature termination codon (PMID: 23913538). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV002352075 SCV001187612 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-07-29 criteria provided, single submitter clinical testing The c.6579+18A>G intronic variant results from an A to G substitution 18 nucleotides after coding exon 42 in the NF1 gene. This alteration has been identified in one individual diagnosed with or suspect of having neurofibromatosis type 1. Further analysis by RT-PCR followed by cDNA sequencing showed this alteration created a cryptic 5' splice site which resulted in the out of frame retention of the first 17 nucleotides of intron 42 (reported as IVS 34 - Legacy numbering in Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV001575829 SCV001802901 likely pathogenic not provided 2022-02-10 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: abnormal splicing (Sabbagh et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS34+18A>G; This variant is associated with the following publications: (PMID: 23913538)
Institute of Medical Genetics, University of Zurich RCV000660095 SCV002569057 pathogenic Neurofibromatosis, type 1 2022-05-22 criteria provided, single submitter clinical testing

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