ClinVar Miner

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

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046745 SCV000074758 benign Cystic fibrosis 2019-12-31 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 RCV000243402 SCV000601084 uncertain significance not specified 2017-04-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000243402 SCV000602993 uncertain significance not specified 2018-07-05 criteria provided, single submitter clinical testing The CFTR c.2991G>C; p.Leu997Phe variant (rs1800111) has been identified in multiple patients 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 it is observed in the general population at a frequency of 0.2% (611/276606 alleles, 1 homozygote) 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 Genetic Testing 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
Integrated Genetics/Laboratory Corporation of America RCV000243402 SCV000919167 benign not specified 2018-12-18 criteria provided, single submitter clinical testing Variant summary: Variant summary: The CFTR c.2991G>C (p.Leu997Phe) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a damaging outcome. This variant was found in 287/125360 control chromosomes at a frequency of 0.0022894, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0062697). The variant has been seen in patients with a wide range of CFTR-related phenotypes; it is also found in ~ 1% of normal alleles from various studies (which could reflect carrier frequency), but of note, two homozygote individuals, one completely unaffected (Derichs_2005) and one only affected with ABPA (Lebecque_2011) have been reported, suggesting it to be a normal variant. The variant has also been found to be in cis with other CFTR deleterious variants such as deltaF508 and c.exon2_exon9del (Fanen_1992 and Schneider_2007) and in cis with R117L (unknown significance) in CF patients, suggesting that it may form part of a complex allele that is responsible for disease. The determination of non CF-causing does not exclude the possibility that this mutation may contribute to CF-like symptoms in certain individuals. In some cases, patients with this mutation (combined with a CF-causing mutation) may develop mild symptoms in select organ systems and/or be diagnosed as having a CFTR-related disorder (CFTR-RD). In addition, functional studies suggests the variant of interest could play a role in bicarbonate permeability that could affect other 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. Taken together, this variant at this time is not expected to result in symptoms that fulfill the diagnostic criteria for CF, and, therefore, the variant of interest has been classified as a Normal Variant/Benign.
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 2019-02-25 criteria provided, single submitter clinical testing Conflicting evidence
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.
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

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