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

gnomAD frequency: 0.00003  dbSNP: rs193922501

Total submissions: 16

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	2024-06-17	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. 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). The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 9439669, 19897426, 15758663, 18306312, 17594398, 20351098, 19724303, 17594397, 20351101, 17235394, 21983161, 19318035, 11938439, 25735457, 27264265, 25658530, 28736296, 29805046, 33374015). ClinVar contains an entry for this variant (Variation ID: 35824). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029477	SCV000074336	pathogenic	Cystic fibrosis	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the CFTR protein (p.Pro5Leu). This variant is present in population databases (rs193922501, gnomAD 0.006%). This missense change has been observed in individuals with bronchiectasis, chronic pancreatitis, cystic fibrosis, and/or other CFTR-related disorders (PMID: 18306312, 19724303, 21520337, 21983161, 25910067). ClinVar contains an entry for this variant (Variation ID: 35824). 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 95%. Experimental studies have shown that this missense change affects CFTR function (PMID: 17235394, 18306312, 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000029477	SCV000220159	likely pathogenic	Cystic fibrosis	2014-03-13	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000727666	SCV000854974	likely pathogenic	not provided	2017-11-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000029477	SCV000886149	pathogenic	Cystic fibrosis	2023-03-30	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	RCV002284179	SCV001169588	pathogenic	Cystic fibrosis; CFTR-related disorder	2020-08-04	criteria provided, single submitter	curation	when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Ambry Genetics	RCV000029477	SCV001172271	likely pathogenic	Cystic fibrosis	2024-01-09	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 http://cftr2.org. 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	likely pathogenic	not provided	2024-06-26	criteria provided, single submitter	clinical testing	The CFTR c.14C>T (p.Pro5Leu) variant is associated with a variable phenotype (see CFTR2 (http://cftr2.org/)). In the published literature, this variant has been reported in individuals with cystic fibrosis (PMIDs: 25658530 (2015), 25754095 (2015), 21983161 (2012), 19724303 (2010), 17331079 (2007), 17137500 (2006), 9439669 (1997)), atypical/mild CF symptoms (PMIDs: 31328366 (2019), 21983161 (2012), 19318035 (2009), 17594397 (2007)), and CFTR-related disorders (PMIDs: 34996830 (2022), 33374015 (2020), 27264265 (2016), 21520337 (2011), 15758663 (2005), 11938439 (2002)). Functional studies indicate this variant has deleterious effects on CFTR protein expression and ion channel activity (PMIDs: 29805046 (2018), 18306312 (2008), 17235394 (2007)). The frequency of this variant in the general population, 0.000054 (7/128930 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Genome-Nilou Lab	RCV000029477	SCV001821978	likely pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000727666	SCV002757301	likely pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on chloride channel activity, protein maturation, and cellular localization (Thelin 2007, Gene 2008, Han 2018, Raraigh 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31036917, 34426522, 29805046, 31328366, 20351101, 20351098, 17235394, 9439669, 25735457, 18306312, 23430892, 25910067, 30134826, 28736296, 27264265, 19897426, 19318035, 17594398, 17331079, 17137500, 33572515, 30046002, 25754095, 25658530, 31776420, 15758663, 21520337, 11938439, 17594397, 19724303, 21983161)
CeGaT Center for Human Genetics Tuebingen	RCV000727666	SCV002821843	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	CFTR: PM3:Very Strong, PM2, PS3:Supporting
Baylor Genetics	RCV003473126	SCV004213361	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727666	SCV004562363	pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	The CFTR c.14C>T; p.Pro5Leu variant (rs193922501) is described as a variant of varying clinical consequences (CFTR2 database). It has been observed in trans with a pathogenic severe variant (i.e. F508del) in individuals who were either asymptomatic, had atypical/mild cystic fibrosis, or were diagnosed with pancreatic sufficient or insufficient cystic fibrosis (CFTR2 database, Casals 1997, Gene 2008, Narzi 2007, Schneider 2007, Spicuzza 2012). Functional characterization of the variant indicates a failure to generate mature CFTR protein and localization to the plasma membrane, and has 10-25% function as wild type protein (Gene 2008, Raraigh 2018, Thelin 2007). This variant is reported in ClinVar (Variation ID: 35824). It is found in the general population with a low overall allele frequency of 0.002% (7/282536 alleles) in the Genome Aggregation Database. The proline at codon 5 is well conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is classified as pathogenic with varying clinical consequences. REFERENCES CFTR2: https://www.cftr2.org/ Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. Gene GG et al. N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel. Hum Mutat. 2008 May;29(5):738-49. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007 Jul;72(1):39-46. Schneider M et al. Large deletions in the CFTR gene: clinics and genetics in Swiss patients with CF. Clin Genet. 2007 Jul;72(1):30-8. 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. Spicuzza L et al. Mild cystic fibrosis in patients with the rare P5L CFTR mutation. J Cyst Fibros. 2012 Jan;11(1):30-3. Thelin WR et al. Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Invest. 2007 Feb;117(2):364-74.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000029477	SCV004809413	likely pathogenic	Cystic fibrosis	2024-04-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734531	SCV005362178	likely pathogenic	CFTR-related disorder	2024-04-03	no assertion criteria provided	clinical testing	The CFTR c.14C>T variant is predicted to result in the amino acid substitution p.Pro5Leu. This variant has been reported in the compound heterozygous state in individuals with cystic fibrosis or chronic pancreatitis, typically with mild features and a second pathogenic variant that has been associated with severe forms of cystic fibrosis such as p.Phe508del (Gené et al. 2008. PubMed ID: 18306312; Thelin et al. 2007. PubMed ID: 17235394; Spicuzza et al. 2012. PubMed ID: 21983161; Steiner et al. 2011. PubMed ID: 21520337). In vitro studies indicate this variant results in impaired CFTR function, presumably through a loss of glycosylation leading to intracellular retention of the receptor (Gené et al. 2008. PubMed ID: 18306312). However, to our knowledge there are no reports of individuals with classic cystic fibrosis who are homozygous for this variant. This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.