ClinVar Miner

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

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000029548 SCV000075298 benign Cystic fibrosis 2020-12-06 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723380 SCV000227132 uncertain significance not provided 2018-06-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000251973 SCV000304505 likely benign not specified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000723380 SCV000601137 uncertain significance not provided 2020-02-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282725 SCV000603008 uncertain significance none provided 2020-03-11 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), bronchiectasis (Guan 2018), and mild pulmonary disorders (Ghanem 1994). Although initial functional studies suggested a defect in CFTR processing and chloride transport activity (Jurkuvenaite 2006), subsequent studies indicated 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. Additionally, another variant at this codon (p.Arg31Leu) has been reported in an individual with elevated sweat chloride levels (Zielenski 1995) and exhibited 56% of wildtype chloride channel activity in functional assays (Raraigh 2018). The arginine at codon 31 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that the p.Arg31Cys variant is deleterious. 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. Guan WJ et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. 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. 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. 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. Zielenski J et al. Identification of six mutations (R31L, 441delA, 681delC, 1461ins4, W1089R, E1104X) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Mutat. 1995;5(1):43-7.
Fulgent Genetics,Fulgent Genetics RCV000515170 SCV000611384 uncertain significance Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Johns Hopkins Genomics, Johns Hopkins University RCV000029548 SCV000992339 benign Cystic fibrosis 2019-02-09 criteria provided, single submitter clinical testing
Mendelics RCV000029548 SCV001137466 likely benign Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001018998 SCV001180298 likely benign Inborn genetic diseases 2018-09-28 criteria provided, single submitter clinical testing Intact protein function observed by in vitro/ex vivo assays;Other data supporting benign classification;Seen in conjunction with two deleterious mutations confirmed in trans in symptomatic individuals
Illumina Clinical Services Laboratory,Illumina RCV001161749 SCV001323650 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.
Nilou-Genome Lab RCV000029548 SCV001781372 uncertain significance Cystic fibrosis 2021-07-14 criteria provided, single submitter clinical testing
Natera, Inc. RCV000029548 SCV001453941 benign Cystic fibrosis 2020-04-15 no assertion criteria provided clinical testing

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