Submissions for variant NM_000492.4(CFTR):c.1673T>C (p.Leu558Ser)

gnomAD frequency: 0.00001  dbSNP: rs193922504

Total submissions: 10

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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029483	SCV000052134	pathogenic	Cystic fibrosis	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1673T>C (p.Leu558Ser) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) and AAA+ ATPase domain of 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 4e-06 in 251088 control chromosomes. c.1673T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Cystic Fibrosis (example, Kuwertz-Broking_1995, Dell Edera_2014, Dugueperoux_2005, Sosnay_2013, Kammesheidt_2006, Lucarelli_2013, Sanchez_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significant reduction in CFTR maturation, though chloride conduction study was not performed (Sosnay_2013). Multiple clinical diagnostic laboratories, the CFTR-2 database and the CFTR-France database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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	RCV000029483	SCV001173154	pathogenic	Cystic fibrosis	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; Kenková 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	RCV001811199	SCV001470796	pathogenic	not 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029483	SCV001585583	pathogenic	Cystic fibrosis	2024-02-16	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 558 of the CFTR protein (p.Leu558Ser). This variant is present in population databases (rs193922504, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital bilateral absence of vas deferens and/or cystic fibrosis (PMID: 7525450, 9401110, 9439669, 10798368, 15638824, 22483971, 25910067). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 35829). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 23974870). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000029483	SCV001905500	pathogenic	Cystic fibrosis	2021-09-07	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Baylor Genetics	RCV003473128	SCV004213561	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-02-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031458	SCV005673332	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-05-08	criteria provided, single submitter	clinical testing