ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2249C>T (p.Pro750Leu) (rs140455771)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078984 SCV000110852 uncertain significance not provided 2017-11-07 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000078984 SCV000281655 likely pathogenic not provided 2014-11-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000855589 SCV000603030 uncertain significance not specified 2018-11-10 criteria provided, single submitter clinical testing The CFTR c.2249C>T; p.Pro750Leu variant (rs140455771) has been reported in individuals with cystic fibrosis (CF), either with or without pancreatic insufficiency (De Wachter 2017, Orozco 2000, SickKids CFTR database, CFTR2 database). In trans to CF-causing pathogenic variants, the p.Pro750Leu variant has also been reported in individuals with congenital bilateral absence of vas deferens (Li 2012) and in individuals exhibiting borderline sweat chloride levels as part of a complex variant with p.Arg352Trp (McGinnis 2005, Soultan 2008). However, the p.Pro750Leu variant has also been found in trans to p.Phe508del in two sisters without significant lung or pancreatic symptoms (Bernat 2017). The p.Pro750Leu variant is listed in ClinVar (Variation ID: 53460) and is observed in the general population with an allele frequency of 0.03% (75/275844 alleles) in the Genome Aggregation Database. The proline at residue 750 is highly conserved, but computational algorithms (PolyPhen-2: benign; SIFT: damaging) are inconclusive on the variant's impact on the protein. Functional assays demonstrate the p.Pro750Leu variant protein exhibits 48.6% of wildtype chloride channel activity (Rareigh 2018), though it is unclear if this defect is clinically significant. Due to conflicting information, the clinical significance of the p.Pro750Leu variant is uncertain at this time. References: CFTR2 database: SickKids CFTR database: Bernat JA et al. Compound Heterozygosity for CFTR phe508del/Pro750Leu in Two Siblings with Normal Sweat Chloride, Lung Function, Growth, and Fecal Elastase. J Pulm Med Respir Res 2017 Jun 8;3:010. De Wachter E et al. What can the CF registry tell us about rare CFTR-mutations? A Belgian study. Orphanet J Rare Dis. 2017 Aug 22;12(1):142. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012; 11(4):316-23. McGinniss M et al. Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. Hum Genet. 2005; 118(3-4):331-8. Orozco L et al. Spectrum of CFTR mutations in Mexican cystic fibrosis patients: identification of five novel mutations (W1098C, 846delT, P750L, 4160insGGGG and 297-1G-->A). Hum Genet. 2000; 106(3):360-5. 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. Soultan Z et al. Sweat chloride testing in infants identified as heterozygote carriers by newborn screening. J Pediatr. 2008; 153(6):857-9.
Integrated Genetics/Laboratory Corporation of America RCV000855589 SCV000696892 uncertain significance not specified 2019-05-10 criteria provided, single submitter clinical testing Variant summary: CFTR c.2249C>T (p.Pro750Leu) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) 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 0.00029 in 252642 control chromosomes, predominantly at a frequency of 0.0006 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00029 vs 0.013), allowing no conclusion about variant significance. c.2249C>T has been reported in the literature, either on its own or along with other CFTR pathogenic variants, in multiple individuals with varying phenotypes ranging from asymptomatic to severe CF, CBAVD, chronic pancreatitis and azoospermia. Orozco et al (2000) reported a patient with a severe phenotype and early onset of the disease who also carried the p.Phe508del mutation on the other chromosome. However, due to the methods utilized for variant detection in this study, the possibility of an undetected pathogenic variant in cis with c.2249C>T cannot be excluded. c.2249C>T has been detected in additional patients carrying other pathogenic variants in trans with phenotypes of CBAVD (Li_2012) and CF (Prontera_2016). McGinnis et al (2005) reported the variant in a neonate with borderline sweat chloride level who carried delF508 on the other allele and p.Arg352Trp (likely pathogenic; LabCorp) on the same allele as the variant. A different study detected the variant in trans with p.Phe508del in two sisters that had minimal respiratory symptoms, normal growth parameters and laboratory testing after clinical follow up for several years (Bernat_2017). Experimental evidence evaluating an impact on protein function demonstrated the variant protein to have about 50% of wild type function (Raraigh_2018). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and once as likely pathogenic. The reputable CFTR2 database comments that this variant has varying consequences and some patients with this variant and another CF-causing variant have CF while others do not. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Counsyl RCV000675059 SCV000800517 uncertain significance Cystic fibrosis 2017-04-19 criteria provided, single submitter clinical testing
Mendelics RCV000675059 SCV000886150 likely pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000675059 SCV000915207 likely pathogenic Cystic fibrosis 2018-11-30 criteria provided, single submitter clinical testing The CFTR c.2249C>T (p.Pro750Leu) missense variant has been reported in three studies and in a total of three patients with CFTR-related disorders, all in a compound heterozygous state (Orozco et al. 2000; Storm et al. 2007; Li et al. 2012). Phenotypes included cystic fibrosis including pancreatic insufficiency, classic CF, and congenital absence of the vas deferens and the variant on the second allele was p.Phe508del in at least two of the patients. Control data are unavailable for this variant, which is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Pro750Leu variant is classified as likely pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078984 SCV001134126 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004472 SCV001163517 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009488 SCV001169583 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001014920 SCV001175693 likely pathogenic Inborn genetic diseases 2019-07-05 criteria provided, single submitter clinical testing Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Johns Hopkins Genomics,Johns Hopkins University RCV000675059 SCV001371793 likely pathogenic Cystic fibrosis 2020-01-07 criteria provided, single submitter clinical testing CFTR variant associated with variable clinical consequences. See for phenotype information.

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