Submissions for variant NM_000492.4(CFTR):c.3222T>A (p.Phe1074Leu)

gnomAD frequency: 0.00001  dbSNP: rs186045772

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV000660789	SCV000783028	drug response	ivacaftor response - Efficacy	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Counsyl	RCV000046829	SCV000220505	likely pathogenic	Cystic fibrosis	2014-07-11	criteria provided, single submitter	literature only
GeneDx	RCV000522824	SCV000617533	pathogenic	not provided	2017-07-13	criteria provided, single submitter	clinical testing	The F1074L pathogenic variant in the CFTR gene has been reported previously in cis with the 5T allele in siblings with a mild cystic fibrosis phenotype, but no other variant was found on the opposite CFTR allele (Casals et al., 1997). The F1074L variant has also been reported in cis with the 5T allele and phase unknown with the G551D variant in an individual with congenital bilateral absence of the vas deferens (Casals et al., 2000). Functional studies demonstrate that F1074L is associated with reduced chloride transport (Van Goor et al., 2014). The F1074L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F1074L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. The F1074L variant is reported in the CFTR2 database as being associated with varying consequences. Missense variants in nearby residues (G1069R, R1070Q, R1070W, L1077P) have been reported in the Human Gene Mutation Database in association with cystic fibrosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret F1074L as a pathogenic variant.
Eurofins Ntd Llc (ga)	RCV000522824	SCV000861385	likely pathogenic	not provided	2018-05-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004302	SCV001163179	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046829	SCV001361660	likely pathogenic	Cystic fibrosis	2024-03-21	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3222T>A (p.Phe1074Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-06 in 253492 control chromosomes. The variant has been reported in cis with 5T allele in individuals affected with Non-classic Cystic Fibrosis (Casals_1997, Casals_2000). In those three patients, authors did not find a pathogenic variant in the second allele, however in additional patients with CBVAD or CF, pathogenic variants were detected on second allele (Casals_2000, Terlizzi_2019). Furthermore, other individuals have been reported with a second pathogenic allele who have intermmediate sweat chloride levels, resulting in an inconclusive CF diagnosis (e.g. Colombo_2006, Padoan_2006, Gonska_2021). These data indicate that the variant may be associated with disease. At least one publication reports that this variant leads to impaired chloride transport and processing (Van Goor_2013, Prins_2020), consistent with the mild CF disease associated with this variant. The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 10875853, 9439669, 24813944, 15126740, 8702904, 23017188, 17003641, 26574590, 25033378, 28736296, 30888834, 20416310, 16801189, 32934006, 30561903, 32150665, 23687349, 23891399, 34814176). ClinVar contains an entry for this variant (Variation ID: 53688). Based on the evidence outlined above, the variant was classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000522824	SCV001477710	uncertain significance	not provided	2023-02-07	criteria provided, single submitter	clinical testing	The CFTR c.3222T>A; p.Phe1074Leu variant (rs186045772) is reported in the literature in individuals affected with CFTR-related disorders (CFTR-RD), such as pancreatitis, congenital bilateral absence of the vas deferens, or other mild symptoms (Casals 1997, Casals 2000, Colombo 2007, Coste 2004, Keiles 2006, Ooi 2010, Padoan 2006, see links to CFTR databases). Some of these individuals carried a CF-causing variant on the opposite chromosome, and several individuals were reported to carry the mild 5T variant on the same chromosome. While this indicates that the p.Phe1074Leu variant can be part of a complex variant with 5T ([c.3222T>A;5T]), insufficient information was provided by some of the cited authors to determine whether this is always the case. The p.Phe1074Leu variant is reported in ClinVar (Variation ID: 53688), and it is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.804). Functional analyses of the variant protein show reduced expression and decreased chloride transport (Van Goor 2014). While available evidence suggests that the complex variant [c.3222T>A;5T] is likely pathogenic, the clinical significance of c.3222T>A; p.Phe1074Leu alone is uncertain at this time. References: Link to CFTR2 database: https://cftr2.org/mutation/scientific/pi/F1074L Link to cystic fibrosis mutation database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=457 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. PMID: 9439669. Casals T et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod. 2000 Jul;15(7):1476-83. PMID: 10875853. Colombo C et al. Is early identification of asymptomatic infants with 'mild' CFTR genotypes clinically useful? Acta Paediatr. 2007 Mar;96(3):477-9. PMID: 17407489. Coste A et al. Atypical sinusitis in adults must lead to looking for cystic fibrosis and primary ciliary dyskinesia. Laryngoscope. 2004 May;114(5):839-43. PMID: 15126740. Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Ooi CY et al. Genetic testing in pancreatitis. Gastroenterology. 2010 Jun;138(7):2202-6, 2206.e1. PMID: 20416310. Padoan R et al. Identification of the 5T-12TG allele of the cystic fibrosis transmembrane conductance regulator gene in hypertrypsinaemic newborns. Acta Paediatr. 2006 Jul;95(7):871-3. PMID: 16801189. 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 Jan;13(1):29-36. PMID: 23891399.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000046829	SCV002507355	pathogenic	Cystic fibrosis	2020-06-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000046829	SCV002611358	likely pathogenic	Cystic fibrosis	2023-07-12	criteria provided, single submitter	clinical testing	The p.F1074L variant (also known as c.3222T>A), located in coding exon 20 of the CFTR gene, results from a T to A substitution at nucleotide position 3222. The phenylalanine at codon 1074 is replaced by leucine, an amino acid with highly similar properties. This variant was identified in four individuals in the Italian cystic fibrosis registry; however, full genotype and phenotype information was not provided (Salvatore D et al. Pediatr. Pulmonol., 2019 Feb;54:150-157). An in vitro study suggested that this alteration results in deficient CFTR protein maturation and chloride transport (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). In some cases, this alteration has been reported to occur in cis with the 5T variant (Casals T et al. Hum. Genet., 1997 Dec;101:365-70; Casals T et al. Hum. Reprod., 2000 Jul;15:1476-83). The p.F1074L variant 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 March 11, 2019). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046829	SCV003485255	uncertain significance	Cystic fibrosis	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1074 of the CFTR protein (p.Phe1074Leu). This variant is present in population databases (rs186045772, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of CFTR-related conditions (PMID: 10875853, 16801189, 17003641, 17407489, 32150665, 34814176). ClinVar contains an entry for this variant (Variation ID: 53688). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003474571	SCV004213496	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-02-08	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002228160	SCV002507439	pathogenic	CFTR-related disorder	2020-06-17	no assertion criteria provided	clinical testing