ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2991G>C (p.Leu997Phe) (rs1800111)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 20
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046745 SCV000074758 benign Cystic fibrosis 2020-12-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078991 SCV000226875 pathogenic not provided 2016-08-12 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000243402 SCV000304486 likely benign not specified criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078991 SCV000493335 likely pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
GeneDx RCV000078991 SCV000589481 uncertain significance not provided 2018-12-27 criteria provided, single submitter clinical testing The L997F variant in the CFTR gene has been reported previously in trans with another pathogenic CFTR variant in individuals with cystic fibrosis and atypical cystic fibrosis, as well as in asymptomatic individuals (Lucarelli et al., 2010; Strom et al., 2011; Schippa et al., 2013). It has been suggested that the presence of the R117L variant in cis with L997F as a complex allele may in part explain the variable phenotype observed in individuals with the L997F variant (Lucarelli et al., 2010). The L997F variant is observed in 59/10,146 (0.58%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The L997F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Functional studies demonstrated that the L997F variant was associated with somewhat reduced chloride transport (VanGoor et al., 2014). We interpret L997F as a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078991 SCV000601084 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282719 SCV000602993 uncertain significance none provided 2020-08-27 criteria provided, single submitter clinical testing The CFTR c.2991G>C; p.Leu997Phe variant (rs1800111) has been identified in multiple individuals diagnosed with CFTR-related disorders (Bergougnoux 2015, Gallati 2009, Gomez-Lira 2000, Hamoir 2013, Lucarelli 2010, Masson 2013, Pelletier 2010), but it was not enriched in pancreatitis patients in a case-control study (LaRusch 2014). In addition, individuals homozygous for this variant have been reported to be clinically asymptomatic (Derichs 2005, Stanke 2008, Terlizzi 2017). Functional characterization of the variant protein indicates a reduction in the CFTR chloride transport activity (Bergougnoux 2015, Sosnay 2013, Van Goor 2014), but at a level unlikely to cause cystic fibrosis (Sosnay 2013, Strom 2011). This variant is reported in ClinVar (Variation ID: 7229) and is observed in the general population at a frequency of 0.22% (627/282204 alleles, including 3 homozygotes) in the Genome Aggregation Database. The leucine at codon 997 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. Due to the conflicting information regarding this variant, its clinical significance cannot be determined with certainty. References: Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015; 14(5):646-53. Derichs N et al. Homozygosity for L997F in a child with normal clinical and chloride secretory phenotype provides evidence that this cystic fibrosis transmembrane conductance regulator mutation does not cause cystic fibrosis. Clin Genet. 2005; 67(6):529-31. 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. Gomez-Lira M et al. High frequency of cystic fibrosis transmembrane regulator mutation L997F in patients with recurrent idiopathic pancreatitis and in newborns with hypertrypsinemia. Am J Hum Genet. 2000; 66(6):2013-4. Hamoir C et al. Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants. Digestion. 2013; 87(4):229-39. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014 10(7):e1004376. Lucarelli M et al. A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation. Genet Med. 2010; 12(9):548-55. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013; 8(8):e73522. 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. 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. Stanke F et al. Diversity of the basic defect of homozygous CFTR mutation genotypes in humans. J Med Genet. 2008; 45(1):47-54. Strom C et al. The dangers of including nonclassical cystic fibrosis variants in population-based screening panels: p.L997F, further genotype/phenotype correlation data. Genet Med. 2011; 13(12):1042-4. Terlizzi V et al. Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. J Med Genet. 2017 Apr;54(4):224-235. 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000046745 SCV000782755 uncertain significance Cystic fibrosis 2017-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000046745 SCV000800721 uncertain significance Cystic fibrosis 2017-03-22 criteria provided, single submitter clinical testing
Mendelics RCV000046745 SCV000886143 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000243402 SCV000919167 benign not specified 2020-11-12 criteria provided, single submitter clinical testing Variant summary: CFTR c.2991G>C (p.Leu997Phe) 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 0.0024 in 254424 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0024 vs 0.013), allowing no conclusion about variant significance. c.2991G>C has been reported in the literature in patients with a wide range of atypical CFTR-related phenotypes such as bronchiectasis, pancreatitis, hypertrypsinemia, asthma, renal agenesis without a strong evidence of causality (example, Lebecque_2011, Tzetis_2001, Casals_2000, Padoan_2002); it is also found in ~ 1% of normal alleles from various studies. Of note, two homozygote individuals, one completely unaffected (Derichs_2005) and one only affected with allergic bronchopulmonary aspergillosis (ABPA) (Lebecque_2011) have been reported. The variant has also been found to be in cis with other CFTR deleterious variants such as deltaF508 (Fanen_1992), a large deletion spanning exons 2-9 of the CFTR gene (Schneider_2007, Strom_2011) and with R117L (Lucarelli_2010, classified as likely pathogenic) in CF patients supporting a benign outcome. Lastly, the variant has also been reported as having been co-inherited with a disease causing deletion spanning the entire SPINK1 gene in one family segregating with chronic pancreatitis (Masson_2007, cited in Bombieri_2011) supporting an alternative molecular basis of disease. These data indicate that the variant is unlikely to be associated with CF or any of its related variably expressive disease phenotypes. Reputed databases such as CFTR2 cite this variant as not disease causing (Sosnay_2013). In addition, functional studies suggest the variant could play a role in bicarbonate permeability relevant to organs in which CFTR is used for bicarbonate secretion (LaRush_2014) and has significantly reduced chloride conductance (Van Goor_2013), however the in vivo impact of these functional defects are unknown. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, at-least two other submitters report a benign/likely benign outcome. Based on the evidence outlined above, the variant in isolation was classified as benign for CF and associated phenotypes.
CFTR-France RCV001009470 SCV001169565 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001017826 SCV001178980 uncertain significance Inborn genetic diseases 2020-03-05 criteria provided, single submitter clinical testing The p.L997F variant (also known as c.2991G>C), located in coding exon 19 of the CFTR gene, results from a G to C substitution at nucleotide position 2991. The leucine at codon 997 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported with a range of clinical outcomes, and is known to occur as part of a complex allele p.[R117L;L997F] which may result in a more severe phenotype (Lucarelli M et al. Mol. Med. 2015 Apr;21:257-75). A child who was homozygous for this alteration was described as asymptomatic; in addition, CFTR activity was shown to be normal in sweat gland, upper airways, and distal intestine samples from this individual (Stanke F et al. J. Med. Genet. 2008 Jan;45:47-54). An in vitro study using transfected FRT cells showed no significant changes in mRNA expression, ratio of mature to total CFTR protein, or amount of normal CFTR protein as a result of the p.L997F variant; however, chloride transport was shown to be approximately 25% of wild-type (Van Goor F et al. J. Cyst. Fibros. 2014 Jan;13:29-36). Another study evaluated individuals with this alteration in isolation or as part of the complex allele. Of 33 individuals compound heterozygous for p.L997F and a second mutation, approximately half exhibited monosymptomatic CFTR-related disorders, including: CBAVD, recurrent pancreatitis, and bronchiectasis and the other half were asymptomatic. Two p.L997F homozygotes were described: one with CBAVD and borderline sweats and the other with chronic sinus disease and nasal polyposis. In two sibling pairs with the p.[R117L;L997F] complex allele in trans with a pathogenic mutation, each individual has a diagnosis of pancreatic sufficient cystic fibrosis (CF-PS). Another sibling pair was identified as homozygous for the complex allele: the sister has CF-PS while the brother has isolated CBAVD (Terlizzi V et al. J. Med. Genet. 2017 Apr;54:224-235). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. Since evidence regarding its contribution to disease is conflicting, the clinical significance of this variant remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV001009470 SCV001321895 uncertain significance CFTR-related disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000078991 SCV001714240 uncertain significance not provided 2021-03-26 criteria provided, single submitter clinical testing
Pars Genome Lab RCV000046745 SCV001736787 uncertain significance Cystic fibrosis 2021-05-18 criteria provided, single submitter clinical testing
OMIM RCV000007650 SCV000027851 risk factor Pancreatitis, idiopathic, susceptibility to 2001-01-01 no assertion criteria provided literature only
OMIM RCV000007651 SCV000053490 risk factor Hypertrypsinemia, neonatal, susceptibility to 2001-01-01 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000583195 SCV000692328 uncertain significance Pancreatitis 2015-09-15 no assertion criteria provided clinical testing
MAGI's Lab - Research,MAGI Group RCV001327946 SCV001432724 uncertain significance Infertility no assertion criteria provided provider interpretation

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.