ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1673T>C (p.Leu558Ser) (rs193922504)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000029483 SCV000924266 pathogenic Cystic fibrosis 2018-08-31 reviewed by expert panel research
Counsyl RCV000029483 SCV000798106 pathogenic Cystic fibrosis 2018-02-26 criteria provided, single submitter clinical testing
CFTR-France RCV000029483 SCV001169412 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001012671 SCV001173154 pathogenic Inborn genetic diseases 2019-10-03 criteria provided, single submitter clinical testing The p.L558S pathogenic mutation (also known as c.1673T>C and 1805T>C), located in coding exon 12 of the CFTR gene, results from a T to C substitution at nucleotide position 1673. The leucine at codon 558 is replaced by serine, an amino acid with dissimilar properties. This mutation has been reported in cystic fibrosis patients from Mexico, France, Italy, Spain, Latin America, and the Czech Republic (Orozco L, Hum. Genet. 2000 Mar; 106(3):360-5; Duguépéroux I, Eur. Respir. J. 2005 Mar; 25(3):468-73; Castaldo G, Ann. Hum. Genet. 2005 Jan; 69(Pt 1):15-24; Alonso MJ, Ann. Hum. Genet. 2007 Mar; 71(Pt 2):194-201; Pérez MM, J. Cyst. Fibros. 2007 May; 6(3):194-208; KÃ…â„¢enková P, J. Cyst. Fibros. 2013 Sep; 12(5):532-7). In one study, functional assays demonstrated significantly reduced CFTR activity equal to 1.2% of wild-type levels (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). Based on the available evidence, p.L558S is classified as a pathogenic mutation.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284776 SCV001470796 pathogenic none provided 2019-09-12 criteria provided, single submitter clinical testing The CFTR c.1673T>C; p.Leu558Ser variant (rs193922504) is reported in the literature in multiple patients with cystic fibrosis (Chavez-Saldana 2010, Sosnay 2013, CFTR2 database), or CBAVD when found with a mild CFTR pathogenic variant (Li 2012). Functional analyses of the variant protein show a significant decrease in function (Raraigh 2018, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 35829), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 558 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Link to CFTR2 database: http://cftr2.org/ Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010 62(6):546-52. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 11(4):316-23. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. 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.
Invitae RCV000029483 SCV001585583 pathogenic Cystic fibrosis 2020-02-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 558 of the CFTR protein (p.Leu558Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with cystic fibrosis and in an individual affected with congenital bilateral absence of vas deferens (PMID: 7525450, 9401110, 9439669, 10798368, 15638824, 22483971, 25910067). ClinVar contains an entry for this variant (Variation ID: 35829). Experimental studies have shown that this missense change disrupts the processing of mature CFTR protein compared to wild-type (PMID: 23974870). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029483 SCV000052134 likely pathogenic Cystic fibrosis 2015-10-02 no assertion criteria provided clinical testing

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