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rs75527207

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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

Scores

16
2
1

Clinical Significance

Pathogenic practice guideline P:29O:3

Conservation

PhyloP100: 8.82
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000492.4
PM2
Very rare variant in population databases, with high coverage;
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 id is 7142.Status of the report is reviewed_by_expert_panel, 3 stars.
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 id is 7120.Status of the report is practice_guideline, 4 stars. Variant chr7-117587806-G-A is described in Lovd as [Pathogenic]. Variant chr7-117587806-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFTRNM_000492.4 linkuse as main transcriptc.1652G>A p.Gly551Asp missense_variant 12/27 ENST00000003084.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.1652G>A p.Gly551Asp missense_variant 12/271 NM_000492.4 P2P13569-1

Frequencies

GnomAD3 genomes
AF:
0.000276
AC:
42
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.000175
AC:
44
AN:
250858
Hom.:
0
AF XY:
0.000148
AC XY:
20
AN XY:
135554
show subpopulations
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 SAS 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
show subpopulations
Gnomad4 AFR exome
AF:
0.0000899
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000506
Gnomad4 OTH exome
AF:
0.000415
GnomAD4 genome
AF:
0.000276
AC:
42
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000573
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000444
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:29Other:3
Revision: practice guideline
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:15Other:1
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 18, 2019NM_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. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 29, 2016The 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. -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 28, 2023The 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. -
Pathogenic, reviewed by expert panelresearchCFTR2Mar 17, 2017- -
Pathogenic, criteria provided, single submittercurationCFTR-FranceJan 29, 2018- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsNov 05, 2018- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This 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. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsAug 21, 2023- -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 07, 2012- -
Pathogenic, no assertion criteria providedclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 13, 2015- -
Pathogenic, criteria provided, single submittercurationInstitute of Human Genetics, University of Leipzig Medical CenterSep 05, 2022This 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 -
Pathogenic, practice guidelinecurationAmerican College of Medical Genetics and Genomics (ACMG)Mar 03, 2004- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJun 09, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 06, 2019- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyFeb 10, 2015- -
not provided Pathogenic:8
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 26, 2023This 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. -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicSep 02, 2021- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 03, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 05, 2018The 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. -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 27, 2023The 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. -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
CFTR-related disorders Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Mar 17, 2017- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 06, 2019- -
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
CFTR-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 27, 2023The 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. -
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
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 26, 2022- -
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 30, 2023- -
ivacaftor response - Efficacy Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

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;.;D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
1.0
D;D;D;D
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.96
D;D;D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
4.3
H;.;.;.
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-6.6
D;.;D;.
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;.;D;.
Sift4G
Pathogenic
0.0
D;.;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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs75527207; hg19: chr7-117227860; API