ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3222T>A (p.Phe1074Leu) (rs186045772)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000660789 SCV000783028 drug response ivacaftor response - Efficacy 2018-03-23 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2020-12-21 criteria provided, single submitter clinical testing Variant summary: CFTR c.3222T>A (p.Phe1074Leu) results in a non-conservative amino acid change in 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 (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3222T>A, 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 the fourth patient p.G551D (a known pathogenic variant) was detected in other allele. 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. Three submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic n=1, pathogenic n=1, drug reponse n=1 (expert panel/PharmGKB)). Based on the evidence outlined above, the variant was classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289732 SCV001477710 uncertain significance none provided 2020-04-03 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. The phenylalanine at codon 1074 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. 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: Link to cystic fibrosis mutation database: 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. 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. Colombo C et al. Is early identification of asymptomatic infants with 'mild' CFTR genotypes clinically useful? Acta Paediatr. 2007 Mar;96(3):477-9. 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. Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. Ooi CY et al. Genetic testing in pancreatitis. Gastroenterology. 2010 Jun;138(7):2202-6, 2206.e1. 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. 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.

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