ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1647T>G (p.Ser549Arg)

gnomAD frequency: 0.00001  dbSNP: rs121909005
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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000056350 SCV000087508 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
PharmGKB RCV000211129 SCV000268176 drug response ivacaftor response - Efficacy 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508411 SCV000601054 pathogenic not provided 2017-06-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000056350 SCV000696858 pathogenic Cystic fibrosis 2016-12-08 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1647T>G (p.Ser549Arg) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 120694 control chromosomes and was reported in numerous affected individuals in the literature. Functional studies show the variant to result in defective channel gating as the predominant defect, resulting in less than 1% chloride conductance compared to WT (Yu_2012, Sosnay_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, including CFTR2. Ivacaftor addition caused a >10-fold increase in CFTR-mediated chloride transport in FRT cells expressing S549R-CFTR (Yu_2012) and this drug has been approved by the U.S. Food and Drug Administration to treat patients with CF who are 2 years and older with at least one copy of this mutation (CFTR2 database). Taken together, this variant is classified as pathogenic.
Mendelics RCV000056350 SCV000886187 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University RCV000056350 SCV000891675 pathogenic Cystic fibrosis 2017-12-30 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV000763573 SCV000894412 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2022-02-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004466 SCV001163511 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000056350 SCV001169406 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000056350 SCV001194017 pathogenic Cystic fibrosis 2019-12-09 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.1647T>G(S549R) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870, 10401194 and 18456578. Classification of NM_000492.3(CFTR):c.1647T>G(S549R) 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.
Invitae RCV000056350 SCV001581984 pathogenic Cystic fibrosis 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 549 of the CFTR protein (p.Ser549Arg). This variant is present in population databases (rs121909005, gnomAD 0.006%). This missense change has been observed in individual(s) with cystic fibrosis or congenital absence of the vas deferens (PMID: 10923036, 11005149, 16840743, 23082198). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 40190). 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: 1712898, 10764788, 12080183, 23974870). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000056350 SCV002574029 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: Criteria applied: PS1, PS3_MOD, PM2, PM3_STR, PM5_STR, PP3, PP4
Ambry Genetics RCV000056350 SCV002703801 pathogenic Cystic fibrosis 2023-05-10 criteria provided, single submitter clinical testing The p.S549R pathogenic mutation (also known as c.1647T>G and 1779T>G), located in coding exon 12 of the CFTR gene, results from a T to G substitution at nucleotide position 1647. The serine at codon 549 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been described in the homozygous state in 15 individuals of Middle Eastern descent with pancreatic insufficiency, severe pulmonary disease, and elevated sweat chloride levels (Frossard PM et al. Eur. Respir. J., 1999 Jan;13:100-2). This pathogenic mutation is associated with elevated sweat chloride levels and pancreatic insufficiency; in vitro functional studies showed this mutation results very little to no to chloride conductance compared to wild type (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.
CeGaT Center for Human Genetics Tuebingen RCV000508411 SCV002821845 pathogenic not provided 2022-11-01 criteria provided, single submitter clinical testing CFTR: PM3:Very Strong, PM2, PP3
Baylor Genetics RCV003473249 SCV004213435 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-08-08 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV001826538 SCV004731598 pathogenic CFTR-related disorder 2023-12-19 criteria provided, single submitter clinical testing The CFTR c.1647T>G variant is predicted to result in the amino acid substitution p.Ser549Arg. This variant has been documented as causative for cystic fibrosis (Kerem et al. 1990. PubMed ID: 2236053; Table S2 - Sosnay et al. 2013. PubMed ID: 23974870; This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. In summary, this variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000056350 SCV004804852 pathogenic Cystic fibrosis 2024-03-17 criteria provided, single submitter research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000508411 SCV001743251 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000508411 SCV001954278 pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV001826538 SCV002080631 pathogenic CFTR-related disorder 2017-03-17 no assertion criteria provided clinical testing

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