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

gnomAD frequency: 0.00001  dbSNP: rs121909005

Total submissions: 20

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.
Labcorp Genetics (formerly Invitae), Labcorp	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: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. 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	2024-02-22	criteria provided, single submitter	clinical testing
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
PreventionGenetics, part of Exact Sciences	RCV001826538	SCV004731598	pathogenic	CFTR-related disorder	2023-12-19	no assertion criteria provided	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; cftr2.org). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. In summary, this variant is interpreted as pathogenic.