ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2252-1G>C

dbSNP: rs587781577
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129613 SCV000184402 likely pathogenic Hereditary cancer-predisposing syndrome 2013-09-06 criteria provided, single submitter clinical testing ​The c.2252-1G>C intronic variant results from a G to C substitution one nucleotide before coding exon 19 of the NF1 gene. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected once in our clinical cohort (includes this individual). Based on nucleotide sequence alignment, this position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration creates a new alternate splice acceptor site that is weaker than the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice acceptor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.2252-1G>C variant is classified as likely pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001290876 SCV001479111 pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001290876 SCV002561737 likely pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001290876 SCV003442615 pathogenic Neurofibromatosis, type 1 2022-04-12 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 141209). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 12872266; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 18 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).

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