ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3154T>G (p.Phe1052Val) (rs150212784)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000660777 SCV000783016 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.
Invitae RCV000046799 SCV000074812 uncertain significance Cystic fibrosis 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with valine at codon 1052 of the CFTR protein (p.Phe1052Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is present in population databases, including one homozygous individual (rs150212784, ExAC 0.1%). This variant has been reported in individuals affected with cystic fibrosis, congenital absence of the vas deferens, pancreatitis, pancreatic cancer, and bronchiectasis (PMID: 9239681, 20460946, 18373402, 12439892, 17489851, 19885835, 12843327). However, this variant has also been reported to co-occur with p.Phe508del in at least one asymptomatic individual with borderline sweat chloride levels (PMID: 24204751) and with mild pathogenic variants in individuals with normal sweat chloride tests (PMID: 19885835, 11883825, 10801389, 19318035). ClinVar contains an entry for this variant (Variation ID: 35865). Experimental studies in cultured cells have shown that CFTR protein with this missense variant retains ~87% of chloride transport activity relative to wild-type protein (PMID: 23891399, 26823392, 23974870). By comparison, most severe pathogenic variants, such as p.Phe508del, exhibit ~0-1% transport activity in these same assays. The clinical impact of this small effect on protein function is currently unknown. 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224816 SCV000280878 pathogenic not provided 2015-03-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000224816 SCV000601088 likely pathogenic not provided 2019-04-15 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Results on protein functions were inconclusive.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224816 SCV000700272 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000224816 SCV000883565 pathogenic not provided 2017-07-07 criteria provided, single submitter clinical testing The CFTR c.3154T>G; p.Phe1052Val variant (rs150212784) is reported in patients diagnosed with cystic fibrosis (Brancolini 1995, Lakeman 2008, Mercier 1993, Onay 1998, Sosnay 2013) or CFTR-related disorders (Gallati 2009, Pelletier 2010, Puechal 2011, Tzetis 2007), and associated with varying clinical consequences (CFTR2 database). Functional studies indicate that the variant protein has normal maturation and conductance (Sosnay 2013, Van Goor 2014), but altered channel kinetics (Cotten 1996, Seibert 1996). This variant is reported in ClinVar (Variation ID: 35865), and found in the general population with an overall allele frequency of 0.06% (168/276130 alleles, including 1 homozygote) in the Genome Aggregation Database. The phenylalanine at codon 1052 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 with a variable presentation of clinical phenotypes. REFERENCES CFTR2 database: Brancolini V et al. Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations. Hum Genet. 1995; 96(3):312-8. Cotten J et al. Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1996; 271(35):21279-84. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. Lakeman P et al. CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening. Genet Test. 2008;12(1):25-35. Mercier B et al. Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene. Genomics. 1993; 16(1):296-7. Onay T et al. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998; 102(2):224-30. Pelletier A et al. CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology. 2010; 10(2-3):158-64. Puechal X et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis. 2011; 70(4):653-9. Seibert F et al. Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity. J Biol Chem. 1996; 271(25):15139-45. 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. Tzetis M et al. Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis. Clin Genet. 2007; 71(5):451-7. 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; 13(1):29-36.
Mendelics RCV000046799 SCV000886354 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000770985 SCV000897972 uncertain significance Hereditary pancreatitis 2018-04-27 criteria provided, single submitter clinical testing This recessive variant was identified in a patient with repetitive pancreatitis. The patient harbours also a second variant (see above) in this gene in compound heterozygosity
Johns Hopkins Genomics,Johns Hopkins University RCV000046799 SCV000992329 likely pathogenic Cystic fibrosis 2019-03-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000046799 SCV000052171 likely pathogenic Cystic fibrosis 2015-10-02 no assertion criteria provided clinical testing

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