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

gnomAD frequency: 0.00022  dbSNP: rs75527207

Total submissions: 32

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	2022-12-15	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	2024-03-25	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