7-117509123-G-A

Position:

chr7-117509123-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):c.254G>A(p.Gly85Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000634 in 1,593,676 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. G85R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic practice guideline P:24O:1

Conservation

PhyloP100: 7.71

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]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 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 chr7-117509123-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 53510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

PP5

Variant 7-117509123-G-A is Pathogenic according to our data. Variant chr7-117509123-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7143.Status of the report is practice_guideline, 4 stars. Variant chr7-117509123-G-A is described in Lovd as [Pathogenic]. Variant chr7-117509123-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.254G>A	p.Gly85Glu	missense_variant	3/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.254G>A	p.Gly85Glu	missense_variant	3/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250880

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135624

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:

0.0000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000645

AC:

AN:

1441558

Hom.:

Cov.:

AF XY:

0.0000612

AC XY:

AN XY:

718684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000823

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Other:1

Revision: practice guideline

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:10Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 19, 2021	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1991	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 85 of the CFTR protein (p.Gly85Glu). This variant is present in population databases (rs75961395, gnomAD 0.009%). This missense change has been observed in individuals with cystic fibrosis and other CFTR-related conditions (PMID: 1710599, 9271620, 15176679, 19885835, 22020151, 23891399, 23974870). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7143). 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: 21998193). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 27, 2022	The p.G85E pathogenic mutation (also known as c.254G>A), located in coding exon 3 of the CFTR gene, results from a G to A substitution at nucleotide position 254. The glycine at codon 85 is replaced by glutamic acid, an amino acid with similar properties. This mutation was first described in a pancreatic insufficient individual with cystic fibrosis with a second CFTR mutation in trans (Zielenski J et al. Genomics, 1991 May;10:229-35). This mutation results in failure of protein maturation and chloride conductance, and is associated with a severe disease phenotype (Decaestecker K et al. Eur. Respir. J., 2004 May;23:679-84; Gené GG et al. Hum. Mutat., 2008 May;29:738-49). In a cohort of 201 patients with this mutation, elevated sweat chloride levels, pulmonary disease, and pancreatic insufficiency were reported in the majority of individuals (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 15, 2019	NM_000492.3(CFTR):c.254G>A(G85E) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.254G>A(G85E) 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. -

not provided

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 24, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 25, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 27, 2021	This variant has been reported in individuals affected with Cystic Fibrosis and Cystic Fibrosis Related Disorders (CFRD) in the published literature (PMID: 32429104 (2020), 28603918 (2017), 23891399 (2014), 23974870 (2013), 23951356 (2013), 22658665 (2012), 22020151 (2012), 18456578 (2008)). In addition, this variant has been shown to have a damaging effect on CFTR protein function (PMID: 32204475 (2020), 24440181 (2014), 23891399 (2014), 15176679 (2004)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2019	The CFTR c.254G>A; p.Gly85Glu variant (rs75961395) is reported in multiple unrelated patients diagnosed with cystic fibrosis (Chalkley 1991, Chavez-Saldana 2010, Gallati 2009, Kerem 1997, Ooi 2012, Zielenski 1991, CFTR2 database). However, the clinical presentations of these patients are highly variable, ranging from severe lung disorder and pancreatic insufficiency, to mild respiratory symptoms and pancreatic sufficiency (Chalkley 1991, Kerem 1997). Functional characterization of the variant protein indicates a failure in trafficking to the cell surface (Patrick 2011, Sosnay 2013, Van Goor 2014), due to aberrant integration of the protein in the endoplasmic reticulum (Patrick 2011). The variant is described in the ClinVar database (Variation ID: 7143) and in the Genome Aggregation Database in 12 out of 276578 alleles. The glycine at residue 85 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has a deleterious impact on the protein. Considering available information, the variant is classified as pathogenic. References: Link to CFTR2 database: http://cftr2.org/ Chalkley G et al. A cystic fibrosis patient who is homozygous for the G85E mutation has very mild disease. J Med Genet. 1991 28(12):875-7. Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010 62(6):546-52. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 19(5):685-94. Kerem B et al. A missense cystic fibrosis transmembrane conductance regulator mutation with variable phenotype. Pediatrics. 1997 100(3):E5. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. Patrick A et al. Alteration of CFTR transmembrane span integration by disease-causing mutations. Mol Biol Cell. 2011 22(23):4461-71. 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. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 13(1):29-36. Zielenski J et al. Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1991 May;10(1):229-35. -

CFTR-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 13, 2024	The CFTR c.254G>A variant is predicted to result in the amino acid substitution p.Gly85Glu. This variant has been reported in unrelated patients with cystic fibrosis, pancreatic insufficiency, and congenital bilateral absence of vas deferens (Chalkley et al. 1991. PubMed ID: 1757965; Gallati et al. 2009. PubMed ID: 20021716; Ooi and Durie. 2012. PubMed ID: 22658665; Masson et al. 2013. PubMed ID: 23951356; Sosnay et al. 2013. PubMed ID: 23974870; cftr2.org). Functional studies showed that the p.Gly85Glu substitution leads to defects in CFTR protein processing resulting from the aberrant integration into the endoplasmic reticulum membrane and failure in trafficking to the cell surface (Patrick et al. 2011. PubMed ID: 21998193; Van Goor et al. 2014. PubMed ID: 23891399). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

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 14, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

.;D;.;.;D;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.0

.;M;.;.;.;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.4

D;D;.;.;D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;.;.;D;.

Sift4G

Pathogenic

0.0

D;D;.;.;D;.

Polyphen

0.99

.;D;.;.;.;.

Vest4

0.97

MVP

1.0

MPC

0.012

ClinPred

0.90

GERP RS

5.7

Varity_R

0.99

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over