Total submissions: 28
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
American College of Medical Genetics and Genomics |
RCV000007559 | SCV000071388 | pathogenic | Cystic fibrosis | 2004-03-03 | practice guideline | curation | Converted during submission to Pathogenic. |
CFTR2 | RCV000007559 | SCV000071519 | pathogenic | Cystic fibrosis | 2017-03-17 | reviewed by expert panel | research | |
Invitae | RCV000007559 | SCV000074204 | pathogenic | Cystic fibrosis | 2023-12-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 334 of the CFTR protein (p.Arg334Trp). This variant is present in population databases (rs121909011, gnomAD 0.02%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 15371902). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7139). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 23974870). For these reasons, this variant has been classified as Pathogenic. |
Center for Pediatric Genomic Medicine, |
RCV000224060 | SCV000281464 | pathogenic | not provided | 2015-02-11 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV001000033 | SCV000603018 | pathogenic | not specified | 2019-02-08 | criteria provided, single submitter | clinical testing | The CFTR c.1000C>T; p.Arg334Trp variant (rs121909011) is reported in numerous individuals affected with cystic fibrosis and is often associated with pancreatic sufficiency (Antinolo 1997, Ooi 2012, Sosnay 2013, CFTR2 database). Many affected individuals have been reported to carry an additional pathogenic variant in trans (Antinolo 1997). Functional characterization of p.Arg334Trp variant protein indicates substantial defects in chloride transport activity (Sosnay 2013, Van Goor 2014). This variant is reported as pathogenic in ClinVar (7139), and it is found in the general population with an overall allele frequency of 0.006% (16/282602 alleles) in the Genome Aggregation Database. The arginine at codon 334 is highly conserved, and computational algorithms (SIFT, PolyPhen2) predict this variant to be damaging to the protein. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Antinolo G et al. Genotype-phenotype relationship in 12 patients carrying cystic fibrosis mutation R334W. J Med Genet. 1997 Feb;34(2):89-91. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;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 Oct;45(10):1160-7. 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 Jan;13(1):29-36. |
Institute Of Human Genetics Munich, |
RCV000007559 | SCV000680167 | pathogenic | Cystic fibrosis | 2017-09-08 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000007559 | SCV000696813 | pathogenic | Cystic fibrosis | 2017-02-23 | criteria provided, single submitter | clinical testing | Variant summary: The CFTR c.1000C>T (p.Arg334Trp) variant located in the ABC transporter type 1, transmembrane domain (via InterPro) involves the alteration of a conserved nucleotide, which 5/5 in silico tools predict a damaging outcome. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 8/121330 (1/15174), which does not exceed the estimated maximal expected allele frequency for a pathogenic CFTR variant of 1/77. The variant of interest has been reported by multiple affected individuals and has been established as a common disease variant, along with being indicated to be on the ACMG variant report list. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. |
Genomic Research Center, |
RCV000007559 | SCV000746379 | pathogenic | Cystic fibrosis | 2017-12-03 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000007559 | SCV000886179 | pathogenic | Cystic fibrosis | 2018-11-05 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000763567 | SCV000894406 | pathogenic | Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000224060 | SCV001134105 | pathogenic | not provided | 2019-08-11 | criteria provided, single submitter | clinical testing | The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. |
Baylor Genetics | RCV001004246 | SCV001163122 | pathogenic | Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation | criteria provided, single submitter | clinical testing | ||
CFTR- |
RCV000007559 | SCV001169454 | pathogenic | Cystic fibrosis | 2018-01-29 | criteria provided, single submitter | curation | |
Myriad Genetics, |
RCV000007559 | SCV001193984 | pathogenic | Cystic fibrosis | 2019-12-20 | criteria provided, single submitter | clinical testing | NM_000492.3(CFTR):c.1000C>T(R334W) is classified as pathogenic and is a non-classic variant in the context of cystic fibrosis. Sources cited for classification include the following: PMID: 23974870. Classification of NM_000492.3(CFTR):c.1000C>T(R334W) 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. |
Genome- |
RCV000007559 | SCV001810331 | pathogenic | Cystic fibrosis | 2021-07-22 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000224060 | SCV002019225 | pathogenic | not provided | 2022-07-20 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV000224060 | SCV002525767 | pathogenic | not provided | 2022-01-14 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000007559 | SCV002573907 | 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_MOD, PM2_SUP, PM3_STR, PM5_STR, PP3 |
Ambry Genetics | RCV000007559 | SCV002646085 | pathogenic | Cystic fibrosis | 2022-06-17 | criteria provided, single submitter | clinical testing | The p.R334W pathogenic mutation (also known as c.1000C>T), located in coding exon 8 of the CFTR gene, results from a C to T substitution at nucleotide position 1000. The arginine at codon 334 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, 15 individuals compound heterozygous for p.R334W typically had elevated sweat chloride levels, recurrent pulmonary infections, and compromised lung function; 60% were pancreatic insufficient (Estivill X et al. Hum. Genet., 1995 Mar;95:331-6). Functional analysis showed this pathogenic mutation markedly reduces the amplitude of the CFTR chloride channel current (Sheppard DN et al. Nature, 1993 Mar;362:160-4). This pathogenic mutation is associated with elevated sweat chloride levels and decreased lung function; 40% of individuals were pancreatic insufficient (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
3billion | RCV000007559 | SCV004013469 | pathogenic | Cystic fibrosis | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007139 / PMID: 2045102). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 9039981). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 9039981). Different missense changes at the same codon (p.Arg334Gln, p.Arg334Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053159, VCV000053160 / PMID: 9272157). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. | |
Prevention |
RCV003407295 | SCV004113934 | pathogenic | CFTR-related condition | 2023-12-27 | criteria provided, single submitter | clinical testing | The CFTR c.1000C>T variant is predicted to result in the amino acid substitution p.Arg334Trp. In the homozygous and compound heterozygous states, this variant has been reported as causative for cystic fibrosis in over 400 affected individuals in the CFTR2 database, and its pathogenicity is supported by functional studies (www.CFTR2.org; Van Goor et al. 2014. PubMed ID: 23891399). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. Based on the available evidence, this variant is interpreted as pathogenic. |
Baylor Genetics | RCV003473017 | SCV004213285 | pathogenic | Bronchiectasis with or without elevated sweat chloride 1 | 2023-10-19 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000007559 | SCV000027760 | pathogenic | Cystic fibrosis | 1997-02-01 | no assertion criteria provided | literature only | |
Gene |
RCV000007559 | SCV001622785 | not provided | Cystic fibrosis | no assertion provided | literature only | ||
Diagnostic Laboratory, |
RCV000224060 | SCV001744660 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000224060 | SCV001956835 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000224060 | SCV001965985 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Natera, |
RCV001826431 | SCV002078177 | pathogenic | CFTR-related disorders | 2017-03-17 | no assertion criteria provided | clinical testing |