ClinVar Miner

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

gnomAD frequency: 0.00022  dbSNP: rs75527207
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Total submissions: 32
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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 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.
Invitae RCV000007540 SCV000074402 pathogenic Cystic fibrosis 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 551 of the CFTR protein (p.Gly551Asp). This variant is present in population databases (rs75527207, gnomAD 0.04%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1379413, 1695717, 2236053, 19734299, 22658665, 23974870, 24066763). 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: 7120). 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: 7493947, 7542778, 8605891). 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.
Eurofins Ntd Llc (ga) 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 RCV000301838 SCV000603048 pathogenic not provided 2023-10-27 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: http://cftr2.org/ 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, Mass General Brigham 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://exac.broadinstitute.org; 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 2023-04-26 criteria provided, single submitter clinical testing This variant has been reported in compound heterozygous individuals affected with cystic fibrosis in the published literature (PMID: 23974870 (2013), 19734299 (2009), 18456578 (2008), 9401006 (1997), 7545856 (1995), 2236053 (1990)). This variant is also associated with chronic pancreatitis and asthma (PMID: 24440239 (2014), 22324837 (2012)). Additionally, multiple studies have shown a damaging effect of this variant on CFTR protein function (PMID: 29805046 (2018), 23891399 (2014), 22293084 (2012), 18167357 (2008), 8605891 (1996)). Therefore, the variant is classified as pathogenic.
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 2022-03-26 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 RCV000007540 SCV001173064 pathogenic Cystic fibrosis 2023-09-28 criteria provided, single submitter clinical testing The c.1652G>A (p.G551D) alteration is located in exon 12 (coding exon 12) of the CFTR gene. This alteration results from a G to A substitution at nucleotide position 1652, causing the glycine (G) at amino acid position 551 to be replaced by an aspartic acid (D). Based on data from gnomAD, the A allele has an overall frequency of 0.018% (51/282242) total alleles studied. The highest observed frequency was 0.04% (51/128786) of European (non-Finnish) alleles. This alteration was first reported in Caucasian individuals with pulmonary disease and pancreatic insufficiency (Cutting, 1990). 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, 1996; Sosnay, 2013). This amino acid position is highly conserved in available vertebrate species. This alteration has been shown to decrease chloride channel activity compared to wild-type CFTR (Bompadre, 2007; Raraigh, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Myriad Genetics, 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 2021-09-02 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000007540 SCV002507340 pathogenic Cystic fibrosis 2019-09-06 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000007540 SCV002573945 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, PM2_SUP, PM3_STR, PM5, PP3, PP4
MGZ Medical Genetics Center RCV000007540 SCV002580125 pathogenic Cystic fibrosis 2022-06-09 criteria provided, single submitter clinical testing
Baylor Genetics RCV000007540 SCV004041226 pathogenic Cystic fibrosis 2023-08-21 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV001831524 SCV004118138 pathogenic CFTR-related disorder 2023-04-27 criteria provided, single submitter clinical testing The CFTR c.1652G>A variant is predicted to result in the amino acid substitution p.Gly551Asp. This variant has been reported to be causative for cystic fibrosis with or without pancreatic insufficiency (Kerem et al 1990. PubMed ID: 2236053; Ooi and Durie. 2012. PubMed ID: 22658665; https://www.ncbi.nlm.nih.gov/books/NBK1250/). Functional studies show this variant results in reduced CFTR-related chloride transport compared to control (Jovov et al. 1995. PubMed ID: 7493947; Fulmer et al. 1995. PubMed ID: 7542778; Delaney et al. 1996. PubMed ID: 8605891). This variant is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117227860-G-A). This variant is interpreted as pathogenic.
Baylor Genetics RCV003473009 SCV004211634 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-10-30 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 not provided Hereditary pancreatitis no assertion provided literature only
GeneReviews RCV000007540 SCV001622789 not provided Cystic fibrosis no assertion provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000301838 SCV001743930 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000301838 SCV001957467 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000301838 SCV001964832 pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV001831524 SCV002080636 pathogenic CFTR-related disorder 2017-03-17 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001831524 SCV002507424 pathogenic CFTR-related disorder 2019-09-06 no assertion criteria provided clinical testing

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