ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1040G>C (p.Arg347Pro) (rs77932196)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
American College of Medical Genetics and Genomics (ACMG) RCV000007530 SCV000071389 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
CFTR2 RCV000007530 SCV000071521 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506615 SCV000603032 pathogenic not specified 2018-10-19 criteria provided, single submitter clinical testing The CFTR c.1040G>C; p.Arg347Pro variant (rs77932196) has been reported in multiple patients diagnosed with cystic fibrosis (Chavez-Saldana 2010, Dean 1990, Ivady 2011) and is associated with both pancreatic-sufficient and -insufficient disease (Dean 1990, Ooi 2012, CFTR2 database). It has also been identified in individuals with congenital bilateral absence of vas deferens and infertility (Amato 2012, Tomaiuolo 2011) when found in-trans with a mildly pathogenic CFTR variant (Tomaiuolo 2011). Functional characterization of the p.Arg347Pro variant protein indicates a failure to generate mature protein, leading to the loss of chloride transport activity (Sosnay 2013, Van Goor 2014). The variant is listed as pathogenic in ClinVar (Variation ID: 7110) and is observed twice in the Exome Variant Server (2/13006 alleles) and 6 times in the Genome Aggregation Database (6/245866 alleles). The arginine at residue 347 is highly conserved (Alamut v2.10), and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that this variant is deleterious. Based on the above information, p.Arg347Pro variant is classified as moderately pathogenic. References: CFTR2 database: Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012; 14(1):81-9. Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010; 62(6):546-52. Dean M et al. Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients. Cell. 1990; 61(5):863-70. Ivady G et al. Distribution of CFTR mutations in Eastern Hungarians: relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis. J Cyst Fibros. 2011; 10(3):217-20. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. 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. Tomaiuolo R et al. Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment. Clin Chem Lab Med. 2011; 49(8):1289-93. 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.
Integrated Genetics/Laboratory Corporation of America RCV000007530 SCV000696817 pathogenic Cystic fibrosis 2017-01-27 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1040G>C (p.Arg347Pro) variant located in the ABC transporter type 1, transmembrane domain (via InterPro) involves the alteration of a conserved nucleotide, which 4/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121338, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant of 1/77. Multiple publications have cited the variant in affected individuals, and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest is a known, well-established common Pathogenic. Therefore, the variant of interest has been classified as "pathogenic."
Mendelics RCV000007530 SCV000886258 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004251 SCV001163127 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000007530 SCV001169458 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Myriad Women's Health, Inc. RCV000007530 SCV001194235 pathogenic Cystic fibrosis 2019-12-20 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.1040G>C(R347P) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 12454843, 23974870, 8535440 and 20448091. Classification of NM_000492.3(CFTR):c.1040G>C(R347P) 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.
Johns Hopkins Genomics,Johns Hopkins University RCV000007530 SCV001425443 pathogenic Cystic fibrosis 2020-02-27 criteria provided, single submitter clinical testing Disease-causing CFTR variant. See for phenotype information.
OMIM RCV000007530 SCV000027731 pathogenic Cystic fibrosis 1991-01-01 no assertion criteria provided literature only

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