Submissions for variant NM_000492.4(CFTR):c.2620-26A>G

gnomAD frequency: 0.00108  dbSNP: rs201716473

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000672705	SCV001981592	uncertain significance	Cystic fibrosis	2018-08-31	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
Eurofins Ntd Llc (ga)	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	2022-12-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587637	SCV001157215	uncertain significance	not provided	2023-09-04	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 transcript 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. PMID: 17331079. Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015; 14(5):646-53. PMID: 25797027. Danziger KL et al. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004; 19(3):540-6. PMID: 14998948. 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. PMID: 18685558. 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. PMID: 25781545. 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. PMID: 17719933. 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. PMID: 9003508. 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. PMID: 27222777.
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	RCV000672705	SCV001177042	likely benign	Cystic fibrosis	2017-06-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Johns Hopkins Genomics, Johns Hopkins University	RCV000672705	SCV001425382	benign	Cystic fibrosis	2020-02-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257388	SCV002529699	likely benign	Hereditary pancreatitis	2020-12-08	criteria provided, single submitter	curation
Baylor Genetics	RCV000672705	SCV002583266	likely benign	Cystic fibrosis		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000587637	SCV003831662	uncertain significance	not provided	2022-09-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001027910	SCV001190633	uncertain significance	CFTR-related disorder	2019-05-20	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000672705	SCV001455993	benign	Cystic fibrosis	2019-06-24	no assertion criteria provided	clinical testing