ClinVar Miner

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

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Total submissions: 5
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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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 2019-12-29 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.
Natera, Inc. RCV000668284 SCV001454034 likely pathogenic Cystic fibrosis 2020-09-16 no assertion criteria provided clinical testing

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