Submissions for variant NM_000492.4(CFTR):c.1001G>T (p.Arg334Leu)

dbSNP: rs397508137

Total submissions: 12

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	RCV001811317	SCV001474475	pathogenic	not 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: 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577441	SCV001581099	pathogenic	Cystic fibrosis	2024-11-04	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. 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.
CFTR-France	RCV002281547	SCV002570012	pathogenic	Cystic fibrosis; CFTR-related disorder	2019-09-12	criteria provided, single submitter	curation	the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577441	SCV002573996	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	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
Ambry Genetics	RCV000577441	SCV002694678	pathogenic	Cystic fibrosis	2024-06-13	criteria provided, single submitter	clinical testing	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000577441	SCV003927218	pathogenic	Cystic fibrosis	2023-04-14	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Baylor Genetics	RCV004566862	SCV005057432	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-02-20	criteria provided, single submitter	clinical testing
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
PreventionGenetics, part of Exact Sciences	RCV004537221	SCV004725177	pathogenic	CFTR-related disorder	2024-02-28	no assertion criteria provided	clinical testing	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.