ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2907A>C (p.Ala969=) (rs377502207)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664492 SCV000788459 uncertain significance Cystic fibrosis 2018-04-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000664492 SCV001360550 likely pathogenic Cystic fibrosis 2019-03-07 criteria provided, single submitter clinical testing Variant summary: CFTR c.2907A>C (p.Ala969Ala) 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: one predicts the variant abolishes a 5' splicing donor site, two predict the variant weakens a 5' donor site. At least one publication reported experimental evidence that this variant affects mRNA splicing, demonstrating in a minigene assay that c.2907A>C led to skipping of exon 17, predicted to result in a frameshift and a premature stop codon (Tian 2016). The variant allele was found at a frequency of 2.4e-05 in 251120 control chromosomes, exclusively observed within the East Asian subpopulation (gnomAD). c.2907A>C has been reported in the literature in a compound heterozygote Chinese individual affected with Cystic Fibrosis (Tian 2016). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000664492 SCV001376542 uncertain significance Cystic fibrosis 2019-10-01 criteria provided, single submitter clinical testing This sequence change affects codon 969 of the CFTR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CFTR protein. This variant is present in population databases (rs377502207, ExAC 0.03%). This variant has been observed in an individual affected with cystic fibrosis who had a second CFTR variant (PMID: 27081564). ClinVar contains an entry for this variant (Variation ID: 549917). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 27081564). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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