ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1475C>T (p.Ser492Phe) (rs121909017)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000007575 SCV000071527 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Counsyl RCV000007575 SCV000485985 likely pathogenic Cystic fibrosis 2016-03-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763571 SCV000894410 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004455 SCV001163500 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000007575 SCV001169484 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007575 SCV001360488 pathogenic Cystic fibrosis 2019-11-22 criteria provided, single submitter clinical testing Variant summary: CFTR c.1475C>T (p.Ser492Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251334 control chromosomes (gnomAD). c.1475C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Wine_2001, Alper_2004, McGinniss_2005, Sheridan_2011, Lakeman_2008, Scotet_2002). These data indicate that the variant is very likely to be associated with disease. Functional study, van Goor_2013, found the variant to significantly impede baseline chloride transport and mature CFTR protein production. Three ClinVar submissions (evaluation after 2014) cite the variant twice as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000007575 SCV001425418 pathogenic Cystic fibrosis 2020-04-22 criteria provided, single submitter clinical testing Disease-causing CFTR variant. See for phenotype information.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286208 SCV001472740 pathogenic none provided 2020-07-09 criteria provided, single submitter clinical testing The CFTR c.1475C>T; p.Ser492Phe variant (rs121909017) is reported in the literature in multiple individuals diagnosed with cystic fibrosis (Ferec 1992, Wine 2001, Sheridan 2011), often associated with pancreatic sufficiency (Sosnay 2013, CFTR2 database). Functional analyses of the variant protein indicate a defect in CFTR processing, resulting in the absence of chloride transport activity (Sosnay 2013, Van Goor 2014). This variant is reported in ClinVar (Variation ID: 7155), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at residue 492 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on the above information, the p.Ser492Phe variant is classified as pathogenic. References: CFTR2 database: Ferec C et al. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nat Genet. 1992 1(3):188-91. Sheridan M et al. CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR. J Med Genet. 2011 48(4):235-41. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 13(1):29-36. Wine J et al. Comprehensive mutation screening in a cystic fibrosis center. Pediatrics. 2001 107(2):280-6.
Invitae RCV000007575 SCV001581769 pathogenic Cystic fibrosis 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 492 of the CFTR protein (p.Ser492Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with other CFTR variants in individuals affected with cystic fibrosis (PMID: 15365999, 27086061, 16189704, 21097845). ClinVar contains an entry for this variant (Variation ID: 7155). This variant has been reported to affect CFTR protein function (PMID: 23974870, 23891399, 30046002, 26864378). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007575 SCV000027776 pathogenic Cystic fibrosis 1992-06-01 no assertion criteria provided literature only
Natera, Inc. RCV000007575 SCV001456075 pathogenic Cystic fibrosis 2020-09-16 no assertion criteria provided clinical testing

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