ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1040G>A (p.Arg347His) (rs77932196)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000007602 SCV000071520 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
PharmGKB RCV000660858 SCV000783097 drug response ivacaftor response - Efficacy 2018-03-27 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
Invitae RCV000007602 SCV000074220 pathogenic Cystic fibrosis 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 347 of the CFTR protein (p.Arg347His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs77932196, ExAC 0.001%). This variant is clearly defined as a Cystic Fibrosis (CF) causative allele (PMID: 23974870) and is included in the American College of Medical Genetics (ACMG) panel of CF variants (PMID: 15371902). ClinVar contains an entry for this variant (Variation ID: 7182). For these reasons, this variant has been classified as Pathogenic.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224726 SCV000281142 pathogenic not provided 2015-04-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508504 SCV000603045 pathogenic not specified 2018-08-09 criteria provided, single submitter clinical testing The CFTR c.1040G>A; p.Arg347His variant (rs77932196), is reported in the literature in multiple individuals affected with the pancreatic sufficient form of cystic fibrosis (Cremonesi 1992, Gallati 2009, Ooi 2012). The variant has also been reported in a compound heterozygous state in individuals with pancreatic insufficiency (de Gracia 2005, Izumikawa 2009) or congenital bilateral absence of vas deferens (Li 2012, Steiner 2011, Ravnik-Glavac 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 7182), and is found in the general population with an overall allele frequency of 0.003% (7/276828 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.1040G>C; p.Arg347Pro, c.1040G>T; p.Arg347Leu) have been reported in individuals with cystic fibrosis and are considered pathogenic (Audrezet 2004, Ooi 2012, Sosnay 2013, Van Goor 2014). Functional analyses of the variant protein shows a reduction of chloride transport activity (Anderson 1991, Clain 2001, Sheppard 1993, Smith 2001, Sosnay 2013, Van Goor 2014). The arginine at codon 347 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that the p.Arg347His variant is deleterious. Based on available information, this variant is considered to be moderately pathogenic. References: Anderson MP et al. Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science. 1991 Jul 12;253(5016):202-5. Audrezet MP et al. Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms. Hum Mutat. 2004 Apr;23(4):343-57. Clain J et al. Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function. J Biol Chem. 2001 Mar 23;276(12):9045-9. Cremonesi L et al. Four new mutations of the CFTR gene (541delC, R347H, R352Q, E585X) detected by DGGE analysis in Italian CF patients, associated with different clinical phenotypes. Hum Mutat. 1992 1(4):314-9. de Gracia J et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005 Jul;60(7):558-63. 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. Izumikawa K et al. Unique mutations of the cystic fibrosis transmembrane conductance regulator gene of three cases of cystic fibrosis in Nagasaki, Japan. Intern Med. 2009;48(15):1327-31. 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 Jul;11(4):316-23. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. Ravnik-Glavac M et al. Study of mutant and polyvariant mutant CFTR genes in patients with congenital absence of the vas deferens. Pflugers Arch. 2000;439(3 Suppl):R53-5. Sheppard DN et al. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature. 1993 Mar 11;362(6416):160-4. Smith SS et al. CFTR: covalent and noncovalent modification suggests a role for fixed charges in anion conduction. J Gen Physiol. 2001 Oct;118(4):407-31. 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. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. 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.
Mendelics RCV000007602 SCV000886207 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004250 SCV001163126 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009366 SCV001169219 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Myriad Women's Health, Inc. RCV000007602 SCV001194221 pathogenic Cystic fibrosis 2019-11-20 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.1040G>A(R347H) is classified as pathogenic in the context of cystic fibrosis and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1040G>A(R347H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Mayo Clinic Laboratories, Mayo Clinic RCV000224726 SCV001714230 pathogenic not provided 2020-12-28 criteria provided, single submitter clinical testing
OMIM RCV000007602 SCV000027803 pathogenic Cystic fibrosis 2018-04-09 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007602 SCV000052118 pathogenic Cystic fibrosis 2015-04-06 no assertion criteria provided clinical testing
Natera, Inc. RCV001027909 SCV001190632 pathogenic CFTR-related disorders 2019-05-20 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000224726 SCV001742642 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000224726 SCV001808782 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000224726 SCV001954714 likely pathogenic not provided no assertion criteria provided clinical testing

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