ClinVar Genomic variation as it relates to human health

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3_VSTR, PM5_STR, PP3, PP4

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 334 of the CFTR protein (p.Arg334Leu). This variant is present in population databases (rs397508137, gnomAD 0.007%). This missense change has been observed in individuals with CFTR-related conditions (PMID: 9272157, 27157324, 30134826). ClinVar contains an entry for this variant (Variation ID: 53160). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects CFTR function (PMID: 12679372, 15130785, 17673962, 30046002). This variant disrupts the p.Arg334 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15371902, 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The p.R334L pathogenic mutation (also known as c.1001G>T), located in coding exon 8 of the CFTR gene, results from a G to T substitution at nucleotide position 1001. The arginine at codon 334 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in a male with congenital bilateral absence of the vas deferens (CBAVD) in conjunction with a second CFTR alteration; however, the phase was not provided (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). Two disease-causing mutations, p.R334W and p.R334Q, have been described in the same codon. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

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: https://www.cftr2.org 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.

The CFTR c.1001G>T variant is predicted to result in the amino acid substitution p.Arg334Leu. This variant is known to disrupt protein function and has been documented as causative for cystic fibrosis (CF) and CF-related disorders (Dörk et al. 1997. PubMed ID: 9272157; Sosnay et al. 2013. PubMed ID: 23974870; Lucarelli et al. 2015. PubMed ID: 25910067; Raraigh et al. 2018. PubMed ID: 29805046; Sofia et al. 2018. PubMed ID: 30134826). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. An alternative nucleotide change affecting the same amino acid (p.Arg334Trp) is a well-established cause of CF and CF-related disorders (Gasparini et al. 1991. PubMed ID: 2045102; Sheppard et al. 1993. PubMed ID: 7680769; Maisonneuve et al. 2004. PubMed ID: 15181620; Watson et al. 2004. PubMed ID: 15371902; Lucarelli et al. 2015. PubMed ID: 25910067; Karimi et al. 2018. PubMed ID: 29850441). This variant is interpreted as pathogenic.