ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2252-2A>G

dbSNP: rs1131691105
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492705 SCV000581305 likely pathogenic Hereditary cancer-predisposing syndrome 2016-02-17 criteria provided, single submitter clinical testing The c.2252-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 19 in 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. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position.To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 110000 alleles tested) in our clinical cohort.This nucleotide position is highly conserved in available vertebrate species. This splice prediction software predicts that this alteration will abolish the native splice acceptor site. Alterations that disrupt the canonical splice acceptor site are typically deleterious in nature (ACMGRecommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007.Genet Med.2008;10:294). As such, the c.2252-2A>G variant is classified as likely pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000660007 SCV000781941 likely pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000660007 SCV000826189 pathogenic Neurofibromatosis, type 1 2023-09-05 criteria provided, single submitter clinical testing 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with neurofibromatosis type I (PMID: 12872266, 17426081; Invitae). ClinVar contains an entry for this variant (Variation ID: 428984). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000660007 SCV001479237 pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000660007 SCV002561735 likely pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000660007 SCV004041483 pathogenic Neurofibromatosis, type 1 2023-08-22 criteria provided, single submitter clinical testing

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