rs75527207

chr7-117587806-G-Achr7-117587806-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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:29 O:3
• Conservation: PhyloP100: 8.82

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]

ACMG classification

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
CFTR	NM_000492.4	c.1652G>A	p.Gly551Asp	missense_variant	12/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1652G>A	p.Gly551Asp	missense_variant	12/27	1	NM_000492.4	P2

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

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 250858 Hom.: 0 AF XY: 0.000148 AC XY: 20 AN XY: 135554

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

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

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:29 Other:3

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:15 Other:1

Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 09, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 13, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Sep 06, 2019	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 10, 2015	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 07, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 29, 2016	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. -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 26, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 27, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2018	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. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

CFTR-related disorder Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Sep 06, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 27, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 26, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 30, 2023

- -

ivacaftor response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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

not provided, no classification provided

literature only

GeneReviews

-

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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

Other links and lift over

dbSNP: rs75527207; hg19: chr7-117227860;