ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1392+2del

dbSNP: rs1597689068
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002319145 SCV001171604 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2018-02-26 criteria provided, single submitter clinical testing The c.1392+2delT intronic pathogenic mutation, results from a deletion of a T two nucleotides downstream of coding exon 12 in the NF1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. A similar variant impacting the same position, c.1392+2T>A (also designated as IVS10a+2T>A), has been identified in a patient with NF1 presenting with plexiform neurofibroma (Kluwe L et al. Hum. Mutat., 2002 Mar;19:309). In addition to this data, 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV002551740 SCV003209011 likely pathogenic Neurofibromatosis, type 1 2022-06-11 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 819072). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 12 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). 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.

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