ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1646G>A (p.Ser549Asn) (rs121908755)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000007536 SCV000071528 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
PharmGKB RCV000211264 SCV000268174 drug response ivacaftor response - Efficacy 2018-03-28 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007536 SCV000696857 pathogenic Cystic fibrosis 2016-04-12 criteria provided, single submitter clinical testing Variant summary: The c.1646G>A variant affects a conserved nucleotide, resulting in amino acid change from Ser to Asn. 4/5 in-silico tools predict this variant to be damaging. This variant is found in 13/120694 control chromosomes at a frequency of 0.0001077, which does not exceed maximal expected frequency of a pathogenic allele (0.0129603). This variant is a well-known pathogenic variant and has been reported in numerous CF patients. Variants affecting same amino acid, i.e. p.Ser549Arg, p.Ser549Ile, have been classified as pathogenic, suggesting Ser549 is critical for CFTR function. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727629 SCV000854905 pathogenic not provided 2018-07-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000727629 SCV001134119 pathogenic not provided 2019-04-13 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. One other pathogenic variant affects the same amino acid. 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 RCV001004465 SCV001163510 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000007536 SCV001167214 pathogenic Cystic fibrosis 2019-09-15 criteria provided, single submitter clinical testing Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See for phenotype information.
CFTR-France RCV000007536 SCV001169405 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Myriad Women's Health, Inc. RCV000007536 SCV001194160 pathogenic Cystic fibrosis 2019-10-18 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.1646G>A(S549N) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 1695717, 18456578, and 23974870. Classification of NM_000492.3(CFTR):c.1646G>A(S549N) 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287867 SCV001474608 pathogenic none provided 2020-04-03 criteria provided, single submitter clinical testing The CFTR c.1646G>A; p.Ser549Asn variant (rs121908755) is reported in the literature as a common variant in individuals affected with cystic fibrosis, and is associated with pancreatic insufficiency (Castellani 2008, Cutting 1990, Masica 2015, Sharma 2015, Sosnay 2013). This variant is also reported in individuals affected with CFTR-related disorders when found with a pathogenic-mild variant on the opposite chromosome (Masson 2013, Ooi 2012, Sharma 2014). This variant is reported in ClinVar (Variation ID: 7116), and is found in the general population with an overall allele frequency of 0.0085% (24/282312 alleles) in the Genome Aggregation Database. The serine at codon 549 is highly conserved and is located in the ATP binding site, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate defects in channel gating and function (Sharma 2015, Yu 2012). Additionally, other variants at this codon (c.1645A>C; p.Ser549Arg, c.1647T>G; p.Ser549Arg) have been reported in individuals with cystic fibrosis and are considered pathogenic (Castellani 2008, Masica 2015, Sosnay 2013). Based on available information, the p.Ser549Asn variant is considered to be pathogenic. References: Castellani C et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008 May;7(3):179-96. Cutting GR et al. A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Nature. 1990 Jul 26;346(6282):366-9. Masica DL et al. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity. Hum Mol Genet. 2015 Apr 1;24(7):1908-17. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 Aug 8;8(8):e73522. Ooi CY and Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. Sharma H et al. Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers. Mol Hum Reprod. 2014 Sep;20(9):827-35. Sharma H et al. Function, pharmacological correction and maturation of new Indian CFTR gene mutations. J Cyst Fibros. 2015 Jan;14(1):34-41. 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. Yu H et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012 May;11(3):237-45.
Invitae RCV000007536 SCV001579470 pathogenic Cystic fibrosis 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 549 of the CFTR protein (p.Ser549Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs121908755, ExAC 0.04%). This variant has been reported as either homozygous or heterozygous with an additional pathogenic allele in numerous individuals affected with cystic fibrosis or congenital absence of the vas deferens (PMID: 23974870, 1695717, 24440181, 22658665, 25042876, 7544319, 29360847, 1721624). This variant is also known as c.1778G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 7116). Experimental studies have shown that this variant causes defective channel gating, resulting in decreased chloride conductance (PMID: 25042876, 22293084, 23974870). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000727629 SCV001713425 pathogenic not provided 2021-03-26 criteria provided, single submitter clinical testing
OMIM RCV000007536 SCV000027737 pathogenic Cystic fibrosis 1990-07-26 no assertion criteria provided literature only

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