7-117587806-G-A

Variant names:

• chr7-117587806-G-A
• rs75527207
• NM_000492.4:c.1652G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.1652G>A​(p.Gly551Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,609,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G551S) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic practice guideline P:31 O:3
• Conservation: PhyloP100: 8.82
• Publications: 1507 publications found

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117587805-G-A is described in ClinVar as Pathogenic|drug_response. ClinVar VariationId is 7142.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 7-117587806-G-A is Pathogenic according to our data. Variant chr7-117587806-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7120.Status of the report is practice_guideline, 4 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1652G>A	p.Gly551Asp	missense	Exon 12 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1652G>A	p.Gly551Asp	missense	Exon 12 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1652G>A	p.Gly551Asp	missense	Exon 12 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.1562G>A	p.Gly521Asp	missense	Exon 11 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 250858 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000404 AC: 589 AN: 1457446 Hom.: 0 Cov.: 28 AF XY: 0.000393 AC XY: 285 AN XY: 725358

African (AFR) AF: 0.0000899 AC: 3 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000506 AC: 561 AN: 1108238

Other (OTH) AF: 0.000415 AC: 25 AN: 60218

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74322

African (AFR) AF: 0.0000724 AC: 3 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.000276

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31 Other:3

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:17 Other:1

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD (v2) <0.01 for a recessive condition (51 heterozygotes, 0 homozygotes); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as CF-causing with treatment option available (PMID: 28711222, LOVD, ClinVar, CFTR2.org); This variant has strong functional evidence supporting abnormal protein function. Functional evidence supporting abnormal protein function, where in epithelial cells less than 10% chloride channel conductance compared to wild-type has been reported (PMID: 23974870); Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a moderate amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from glycine to aspartic acid; This variant is heterozygous; This gene is associated with autosomal recessive disease; Multiple alternative amino acid changes at the same position have been observed in gnomAD v2 (highest allele count: 1 heterozygote, 0 homozygotes); Variant is located in the annotated ABC transporter (DECIPHER); Loss of function is a known mechanism of disease in this gene and is associated with cystic fibrosis (MIM#219700).

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Feb 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Aug 21, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 13, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 03, 2004

American College of Medical Genetics and Genomics (ACMG)

Significance: Pathogenic

Review Status: practice guideline

Collection Method: curation

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Sep 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1652G>A; p.Gly551Asp variant (rs75527207, ClinVar Variation ID: 7120), is the third-most common pathogenic CFTR variant (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. PMID: 1695717 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. PMID: 2236053 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. PMID: 23974870

Feb 10, 2015

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jun 10, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS3,PM5_STR,PP3

Jun 09, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 18, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Sep 06, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 07, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:8

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: PM3:Very Strong, PM5, PM2:Supporting, PP3, PS3:Supporting

Dec 03, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 05, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Apr 26, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Jun 18, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

CFTR-related disorder Pathogenic:3

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. This variant is interpreted as pathogenic.

Sep 06, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Feb 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ivacaftor response - Efficacy Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: 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. Drug-variant association: Efficacy

Hereditary pancreatitis Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		8.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MVP		1.0
MPC		0.015
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs75527207; hg19: chr7-117227860;