ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1652G>A (p.Gly551Asp) (rs75527207)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
American College of Medical Genetics and Genomics (ACMG) RCV000007540 SCV000071395 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
CFTR2 RCV000007540 SCV000071501 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
PharmGKB RCV000211289 SCV000268395 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.
Invitae RCV000007540 SCV000074402 pathogenic Cystic fibrosis 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 551 of the CFTR protein (p.Gly551Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs75527207, ExAC 0.03%). This variant has been reported numerous times in the literature in individuals affected wtih cystic fibrosis (PMID: 2236053, 23974870, 19734299, 22658665, 24066763). This variant is considered one of the most common cystic fibrosis-causing variants in CFTR (PMID: 1695717, 1379413), especially among individuals of European decent. ClinVar contains an entry for this variant (Variation ID: 7120). Experimental studies, including a mouse model, have shown that this variant affects the chloride conductance of the CFTR protein (PMID: 8605891, 7542778, 7493947). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000301838 SCV000329247 pathogenic not provided 2018-11-05 criteria provided, single submitter clinical testing The G551D variant in the CFTR gene is a commonly reported pathogenic variant associated with classical cystic fibrosis and accounts for approximately 1.6% of pathogenic variants reported in the CFTR gene (Kerem et al., 1990; Moskowitz et al., 2008). Consistent with the increased carrier frequency for cystic fibrosis among Caucasian populations (Moskowitz et al., 2008), the NHLBI Exome Sequencing Project reports G551D was observed with a frequency of 0.21% (18/8600) alleles in individuals of European American background; no homozygotes were observed in this cohort. The G551D variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies indicate that G551D results in markedly impaired chloride transport activity, suggesting that G551D results in loss of CFTR chloride channel function ( Jovov et al., 1995). We interpret G551D as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000301838 SCV000330923 pathogenic not provided 2015-12-03 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000007540 SCV000584081 pathogenic Cystic fibrosis 2015-02-10 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999836 SCV000603048 pathogenic none provided 2020-06-25 criteria provided, single submitter clinical testing The CFTR p.Gly551Asp (G551D) variant is the third-most common pathogenic CFTR variant that has been reported (Sosnay 2013, CFTR2 database). It is associated with pancreatic insufficient forms of cystic fibrosis (Cutting 1990, Kerem 1990), with the variant protein showing defects in chloride transport (Sosnay 2013). This variant is considered to cause cystic fibrosis when identified with another pathogenic variant on the opposite chromosome. References: CFTR2 database: Cutting G et al. A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Nature. 1990; 346(6282):366-9. Kerem B et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990; 87(21):8447-51. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000007540 SCV000711289 pathogenic Cystic fibrosis 2016-02-29 criteria provided, single submitter clinical testing The p.Gly551Asp variant in CFTR has been reported in more than 500 individuals w ith CFTR-related disorders, including cystic fibrosis, congenital bilateral abse nce of vas deferens, and chronic pancreatitis (Cutting 1990, Kerem 1990, Mocanu 2010, Sosnay 2013, Muthuswany 2014). This variant has been identified in 0.03% ( 17/66338) of European chromosomes by the Exome Aggregation Consortium (ExAC, htt p://; dbSNP rs75527207). Although this variant has been s een in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidenc e that the p.Gly551Asp variant may impact protein function (Teng 2012). In summa ry, this variant meets our criteria to be classified as pathogenic for CFTR-rela ted disorders based upon case data and functional evidence.
Mendelics RCV000007540 SCV000886153 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000301838 SCV000888067 pathogenic not provided 2016-02-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763574 SCV000894413 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
Baylor Genetics RCV001004467 SCV001163512 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000007540 SCV001169409 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001012592 SCV001173064 pathogenic Inborn genetic diseases 2018-12-18 criteria provided, single submitter clinical testing The p.G551D pathogenic mutation (also known as c.1652G>A), located in coding exon 12 of the CFTR gene, results from a G to A substitution at nucleotide position 1652. The glycine at codon 551 is replaced by aspartic acid, an amino acid with similar properties. This pathogenic mutation was first reported in Caucasian individuals with pulmonary disease and pancreatic insufficiency (Cutting GR et al. Nature, 1990 Jul;346:366-9). Furthermore, this mutation has been shown to decrease chloride channel activity compared to wild-type CFTR (Bompadre SG et al. J. Gen. Physiol., 2007 Apr;129:285-98; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). Individuals compound heterozygous for this mutation and another pathogenic CFTR mutation, or homozygous individuals, exhibit clinical features of cystic fibrosis including, but not limited to: elevated sweat chloride levels, pulmonary disease, and pancreatic insufficiency (Parad RB. J. Med. Genet., 1996 Aug;33:711-3; 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.
Myriad Women's Health, Inc. RCV000007540 SCV001194226 pathogenic Cystic fibrosis 2019-10-18 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.1652G>A(G551D) is classified as pathogenic in the context of cystic fibrosis. G551D is a classic cystic fibrosis variant. Sources cited for classification include the following: PMID: 23974870. Classification of NM_000492.3(CFTR):c.1652G>A(G551D) 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000301838 SCV001713427 pathogenic not provided 2021-03-10 criteria provided, single submitter clinical testing
OMIM RCV000007540 SCV000027741 pathogenic Cystic fibrosis 2012-02-07 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007540 SCV000052132 pathogenic Cystic fibrosis 2015-04-13 no assertion criteria provided clinical testing
GeneReviews RCV000119040 SCV000153746 pathogenic Hereditary pancreatitis 2014-03-13 no assertion criteria provided literature only
GeneReviews RCV000007540 SCV001622789 pathogenic Cystic fibrosis 2017-02-02 no assertion criteria provided literature only

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