ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.91C>T (p.Arg31Cys) (rs1800073)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000723380 SCV000603008 uncertain significance not provided 2018-03-23 criteria provided, single submitter clinical testing The CFTR c.91C>T; p.Arg31Cys variant (rs1800073) is reported in individuals with idiopathic pancreatitis (Bernardino 2000, Gomez-Lira 2001), oligospermia (Gallati 2009), and mild pulmonary disorders (Ghanem 1994). Although initial functional studies suggest a defect in CFTR processing and chloride transport activity (Jurkuvenaite 2006), subsequent studies indicate no defects (Sosnay 2013). In addition, the variant has been reported as a homozygote in an asymptomatic individual (Ghanem 1994), and was shown not to be enriched in patients diagnosed with pancreatitis (LaRusch 2014). This variant is reported in ClinVar (Variation ID: 35893), and found in the general population with an overall allele frequency of 0.2% (447/276630 alleles, including 1 homozygote) in the Genome Aggregation Database. The arginine at codon 31 is moderately conserved, and computational algorithms (Align GVGD, Mutation Taster, PolyPhen2, SIFT) predict that the variant has some impact on the protein. Due to the conflicting information regarding this variant, its clinical significance is uncertain at this time. REFERENCES Bernardino AL et al. Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations. Genet Test. 2000;4(1):69-74. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. Ghanem N et al. Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1994 May 15;21(2):434-6. Gomez-Lira M et al. CFTR and cationic trypsinogen mutations in idiopathic pancreatitis and neonatal hypertrypsinemia. Pancreatology. 2001;1(5):538-42. Jurkuvenaite A et al. Mutations in the amino terminus of the cystic fibrosis transmembrane conductance regulator enhance endocytosis. J Biol Chem. 2006 Feb 10;281(6):3329-34. 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 Jul 17;10(7):e1004376. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723380 SCV000227132 uncertain significance not provided 2018-06-20 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515170 SCV000611384 uncertain significance Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral absence of the vas deferens 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000251973 SCV000329244 uncertain significance not specified 2017-02-16 criteria provided, single submitter clinical testing The R31C variant in the CFTR gene was first identified in the homozygous state in an asymptomatic individual and reported as a benign polymorphism (Ghanem et al., 1994). Other publications have reported this variant in association with disseminated bronchiectasis (Girodon et al., 1997), idiopathic pancreatitis (Gomez Lira et al., 2001), and oligospermia (Gallati et al., 2009), though a second CFTR variant was not identified in these cases. The R31C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R31C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (R31L) was identified in an adult woman with pulmonary symptoms but normal pulmonary function, normal pancreatic function, and repeated abnormal sweat chloride levels (mean value 90.9 mmol/L); no second CFTR variant was identified (Zielenski et al., 1995). Functional studies performed show that R31C affects protein biogenesis, although the defect is not complete (Jurkuvenaite et al., 2006). While the R31C variant has been deemed not to be cystic fibrosis-causing (Sosnay et al., 2013), it is possible this variant may have reduced penetrance in association with CF-related disorders. We interpret R31C as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV000251973 SCV000697055 benign not specified 2016-01-29 criteria provided, single submitter clinical testing Variant summary: c.91C>T affects a conserved nucleotide, resulting in amino acid change from Arg to Cys. 5/5 in-silico tools predict damaging outcome. This variant was found in 214/124456 control chromosomes at a frequency of 0.0017195, including 1 homozygous occurrence. This frequency does not significantly exceed maximal expected frequency of a pathogenic allele (0.0129603) for non-classic CF. This variant has been found in patients with atypical CF, ICP and asthma-like bronchopathy. Variant was also found in healthy individuals, including 1 compound heterozygote with F508del with no symptoms suggestive of CF, 1 homozygous asymptomatic 6 y.o. child with family member presented with asthma-like bronchopathy (Ghanem_1994) and one homozygote in ExAC database. CFTR2 database classified this variant as non-CF-casuing based on clinical and functional data (Sosnay_2013). A case-control study including more than 2000 samples showed odds ratio of this variant associated with pancreatitis was 0.42, suggesting this variant does not increase the risk to develop pancreatitis (LaRusch_2014). Taken together, this variant was classified as Benign.
Invitae RCV000029548 SCV000075298 benign Cystic fibrosis 2018-01-04 criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000029548 SCV000992339 benign Cystic fibrosis 2019-02-09 criteria provided, single submitter clinical testing
PreventionGenetics RCV000251973 SCV000304505 likely benign not specified criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000251973 SCV000601137 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing

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.