ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.14C>T (p.Pro5Leu) (rs193922501)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029477 SCV000052127 pathogenic Cystic fibrosis 2021-06-01 criteria provided, single submitter clinical testing Variant summary: CFTR c.14C>T (p.Pro5Leu) 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 2.4e-05 in 251348 control chromosomes. The variant, c.14C>T, has been reported in the literature in multiple individuals affected with Non-classic Cystic Fibrosis, ICP, and CF (e.g. Chirico_2014, Narzi_2007, Sanz_2010, Schneider_2007, Spicuzza_2011). Multiple authors have indicated that the variant could cause a mild form of CF. These data indicate that the variant is very likely to be associated with disease. Co-occurrence with a pathogenic variant, CFTR 5T_TG11, has been reported (Narzi_2007). At least one publication reports experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting in 10%-30% of normal activity (Thelin_2007, Gene_2008, Raraigh_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic n=4, VUS n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000029477 SCV000074336 uncertain significance Cystic fibrosis 2017-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 5 of the CFTR protein (p.Pro5Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs193922501, ExAC 0.005%). This variant has been reported in trans with a pathogenic variant in several individuals with mild respiratory symptoms, chronic pancreatitis and/or atypical cystic fibrosis (CF) (PMID: 21983161, 18306312, 17594398, 17594397, 25910067). This variant has also been reported in trans with a pathogenic variant in two asymptomatic and fertile adult males (PMID: 21983161) and multiple asymptomatic newborns (PMID: 17594398), which suggests that the p.Pro5Leu variant is not pathogenic. ClinVar contains an entry for this variant (Variation ID: 35824). Experimental studies have demonstrated that this missense variant results in decreased expression, partial mislocalization, and a reduction of channel activity of mature CFTR protein in cell culture (PMID: 18306312, 17235394). However, it is unclear from these studies if the effect of this missense on protein function is clinically significant. In summary, this variant is a rare missense change that has been shown to affect protein function in cell culture but the current clinical evidence for this variant is conflicting, with observations in both affected and unaffected individuals. Therefore, this change has been classified as a Variant of Uncertain Significance.
Counsyl RCV000029477 SCV000220159 likely pathogenic Cystic fibrosis 2014-03-13 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727666 SCV000854974 likely pathogenic not provided 2017-11-20 criteria provided, single submitter clinical testing
Mendelics RCV000029477 SCV000886149 uncertain significance Cystic fibrosis 2021-06-10 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004225 SCV001163101 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009493 SCV001169588 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001011889 SCV001172271 likely pathogenic Inborn genetic diseases 2019-09-23 criteria provided, single submitter clinical testing The p.P5L variant (also known as c.14C>T), located in coding exon 1 of the CFTR gene, results from a C to T substitution at nucleotide position 14. The proline at codon 5 is replaced by leucine, an amino acid with similar properties. This alteration has been detected in multiple individuals carrying a second CFTR alteration (six with p.F508del, two with p.W1282*, and one with p.R347P) with varying disease severity. The majority of individuals had pancreatic sufficiency, mild or no respiratory symptoms, normal lung function, and elevated sweat chloride levels (Spicuzza L et al. J. Cyst. Fibros., 2012 Jan;11:30-3; Sofia VM et al. Mol. Med., 2018 07;24:38). This variant has also been identified in multiple newborns with abnormal newborn screening results (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46; Paracchini V et al. JIMD Rep, 2012 Nov;4:17-23), as well as in an individual with idiopathic chronic pancreatitis (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In two functional studies, this variant demonstrated a reduced level of WT-CFTR protein function; in addition, the protein was predominantly localized intracellularly and demonstrated abnormal channel gating activity (Gené GG et al. Hum. Mutat., 2008 May;29:738-49; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). The p.P5L alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at Accessed January 22, 2018). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000727666 SCV001469497 uncertain significance not provided 2020-03-19 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000029477 SCV001821978 likely pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing

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