ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.7321+1G>T

dbSNP: rs1135402903
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000497052 SCV004099694 likely pathogenic Neurofibromatosis, type 1 2023-09-11 criteria provided, single submitter clinical testing Variant summary: NF1 c.7258+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249652 control chromosomes (gnomAD). c.7258+1G>T has been reported in the literature in at-least one individual affected with Neurofibromatosis Type 1 (example: DeLuca_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 15146469). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000497052 SCV004296808 pathogenic Neurofibromatosis, type 1 2023-05-13 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 431689). This variant is also known as 7259+1G>T. Disruption of this splice site has been observed in individual(s) with neurofibromatosis, type 1 (PMID: 12552569). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 48 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).
Medical Genetics, University of Parma RCV000497052 SCV000588835 likely pathogenic Neurofibromatosis, type 1 2017-02-02 no assertion criteria provided clinical testing

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