ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1001G>T (p.Arg334Leu) (rs397508137)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000577441 SCV000924253 pathogenic Cystic fibrosis 2017-12-08 reviewed by expert panel research
Counsyl RCV000577441 SCV000799678 likely pathogenic Cystic fibrosis 2018-05-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287755 SCV001474475 pathogenic none provided 2019-08-19 criteria provided, single submitter clinical testing The CFTR c.1001G>T; p.Arg334Leu variant (rs397508137) is reported in the compound heterozygous state with another pathogenic variant in individuals with pancreatic insufficient cystic fibrosis (see link to CFTR2 database), and in at least one individual affected with congenital bilateral absence of vas deferens (Dork 1997). This variant is reported in ClinVar (Variation ID: 53160), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 334 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.1000C>T; p.Arg334Trp) has been reported in individuals with cystic fibrosis, and is considered pathogenic (Sosnay 2013). Functional assays show that residue 334 is critical for ion binding, and variants at this codon, including p.Arg334Leu, disrupt channel function (Enquist 2009, Gong 2003, Gong 2004, Raraigh 2018, Zhou 2007). Based on available information, the p.Arg334Leu variant is considered to be pathogenic. References: Link to CFTR2 database: Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 100(3-4):365-77. Enquist K et al. Membrane-integration characteristics of two ABC transporters, CFTR and P-glycoprotein. J Mol Biol. 2009 Apr 17;387(5):1153-64. Gong X and Linsdell P. Molecular determinants and role of an anion binding site in the external mouth of the CFTR chloride channel pore. J Physiol. 2003 Jun 1;549(Pt 2):387-97. Gong X and Linsdell P. Maximization of the rate of chloride conduction in the CFTR channel pore by ion-ion interactions. Arch Biochem Biophys. 2004 Jun 1;426(1):78-82. 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. Zhou JJ et al. Direct and indirect effects of mutations at the outer mouth of the cystic fibrosis transmembrane conductance regulator chloride channel pore. J Membr Biol. 2007 Apr;216(2-3):129-42.
Invitae RCV000577441 SCV001581099 pathogenic Cystic fibrosis 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 334 of the CFTR protein (p.Arg334Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with CFTR-related conditions (PMID: 9272157, 27157324, 30134826). ClinVar contains an entry for this variant (Variation ID: 53160). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 15130785, 17673962, 30046002, 12679372). This variant disrupts the p.Arg334 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15371902, 23974870), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577441 SCV000679071 not provided Cystic fibrosis no assertion provided literature only
Natera, Inc. RCV000577441 SCV001456057 pathogenic Cystic fibrosis 2020-09-16 no assertion criteria provided clinical testing

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