ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2620-26A>G (rs201716473)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000587637 SCV000696912 uncertain significance not provided 2017-04-07 criteria provided, single submitter clinical testing Variant summary: The CFTR c.2620-26A>G variant (alternatively also known as 2752-26A>G) involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 1/5 splice prediction tools predict a creation of new splice acceptor site, however, 5/5 tools predict no significant effect in utilization of the consensus splice acceptor site. Two functional studies show that this variant does not affect normal splicing (Bergougnoux_2015, Giorgi_2015). This variant was found in 145/121484 control chromosomes from ExAC (including one homozygote) at a frequency of 0.0011936, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant of interest has been reported in multiple CF patients without strong evidence for causality (i.e. cosegregation with disease and/or concordant recessive genotype). Meanwhile the patients were not comprehensively tested, therefore a possibility of missing a real pathogenic mutation in same allele as well as its co-occurrence in other allele (in trans) with another pathogenic variant cannot be completely ruled out. One adult patient confirmed to have a mild pathogenic variant in other allele (5T allele in intron 9) had milder clinical features of CF (chronic cough, nasal congestion and postnasal drip present for 3 years) with sweat chloride level <30 mmol/L (Yadav_2016). Pulmonary function testing and fecal elastase level in the patient were within normal limits and chest X-ray and CT of the sinuses were also normal. This variant has also been reported in patients with pulmonary and GI manifestations (such as primary sclerosing cholangitis, inflammatory bowel disease, and diffuse bronchiectasis). A new database gnomAD (which comprises data from ExAC plus individuals undergoing genome sequencing) reports the variants allele frequency in Ashkenazi Jewish at 2.640% (268/10150 chromosomes) including 3 homozygotes, which is an evidence against pathogenicity. In addition, one clinical diagnostic laboratory in ClinVar has classified this variant as likely benign. The variant was classified as polymorphism by a recent publication Bergougnoux_2015 in Journal of Cystic Fibrosis (PMID: 25797027), however is considered to have varying phenotypic consequence by CFTR2 database. Taken together, this variant is classified as VUS-possibly benign.
Counsyl RCV000672705 SCV000797839 likely benign Cystic fibrosis 2018-02-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000730943 SCV000858710 likely benign not specified 2017-12-20 criteria provided, single submitter clinical testing

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