ClinVar Miner

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

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Total submissions: 10
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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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587637 SCV001134130 likely benign not provided 2019-04-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000730943 SCV001157215 uncertain significance not specified 2018-11-06 criteria provided, single submitter clinical testing The CFTR c.2620-26A>G variant (rs201716473), also known as 2752-26A>G, is reported in the literature in individuals with monosymptomatic atypical cystic fibrosis (i.e. congenital bilateral absence of the vas deferens, pancreatitis) and normal to borderline sweat chloride values (Alonso 2007, Danziger 2004, Dequeker 2009, Pall 2007, Tzetis 1997, Yadav 2015). This variant is reported in ClinVar (Variation ID: 53529), and is found in the Ashkenazi Jewish population with an allele frequency of 2.7% (277/10,368 alleles, including 3 homozygotes) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant does not alter splicing. Functional analyses of the variant protein show that this variant does not affect normal splicing (Bergougnoux 2015, Giorgi 2015). While the population frequency suggests that this variant is unlikely to be associated with classic CF, its association with milder phenotypes cannot be ruled out. Thus, due to conflicting information, the clinical significance of the c.2620-26A>G variant is uncertain at this time. References: Alonso MJ et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007; 71(Pt 2):194-201. Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015; 14(5):646-53. Danziger KL et al. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004; 19(3):540-6. Dequeker E et al. Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders--updated European recommendations. Eur J Hum Genet. 2009; 17(1):51-65. Giorgi G et al. Validation of CFTR intronic variants identified during cystic fibrosis population screening by a minigene splicing assay. Clin Chem Lab Med. 2015; 53(11):1719-23. Pall H et al. Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function. J Pediatr. 2007; 151(3):255-9. Tzetis M et al. Characterization of more than 85% of cystic fibrosis alleles in the Greek population, including five novel mutations. Hum Genet. 1997; 99(1):121-5. Yadav H et al. Chronic cough with normal sweat chloride: Phenotypic descriptions of two rare cystic fibrosis genotypes. Respir Med Case Rep. 2015; 17:17-9.
Baylor Genetics RCV001004482 SCV001163527 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000672705 SCV001169169 benign Cystic fibrosis 2018-03-26 criteria provided, single submitter curation the variant does not result in CFTR-RD neither
Ambry Genetics RCV001016125 SCV001177042 likely benign Inborn genetic diseases 2017-06-14 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Sub-population frequency in support of benign classification (not ava blue, manual h-w)
Johns Hopkins Genomics,Johns Hopkins University RCV000672705 SCV001425382 benign Cystic fibrosis 2020-02-10 criteria provided, single submitter clinical testing
Natera Inc RCV001027910 SCV001190633 uncertain significance CFTR-related disorders 2019-05-20 no assertion criteria provided clinical testing

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