ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.869+5G>A (rs533959068)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668284 SCV000792858 uncertain significance Cystic fibrosis 2017-07-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781277 SCV000919190 likely pathogenic not specified 2018-05-24 criteria provided, single submitter clinical testing Variant summary: CFTR c.869+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Raynal_2013). The variant allele was found at a frequency of 8.2e-06 in 243092 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-related diseases (8.2e-06 vs 1.30e-02), allowing no conclusion about variant significance. The variant, c.869+5G>A, has been reported in the literature in individuals affected with CF and CBAVD (Girardet_2007, Goh_2007). These data indicate that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. The CFTR-France database cites the variant in a CF patient with classification of 'disease-causing' and UMD and Sickkids cite the variant in a CF patient with deltaF508 in trans. Based on the evidence outlined above, the variant was classified as likely pathogenic.
CFTR-France RCV000668284 SCV001169323 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Invitae RCV000668284 SCV001233424 likely pathogenic Cystic fibrosis 2019-12-30 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs533959068, ExAC 0.01%). This variant has been observed in individual(s) with CFTR-related conditions (PMID: 17398169, 23381846). This variant is also known as 1001+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 552934). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23381846). 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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