chr7-117530918-A-G

Position:

chr7-117530918-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.293A>G(p.Gln98Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,730 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 (★★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15

Conservation

PhyloP100: 8.87

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 transmembrane_region Helical; Name=1 (size 20) in uniprot entity CFTR_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 7-117530918-A-G is Pathogenic according to our data. Variant chr7-117530918-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 53606.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117530918-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.293A>G	p.Gln98Arg	missense_variant	4/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.293A>G	p.Gln98Arg	missense_variant	4/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251054

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460552

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726676

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000896

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:8

Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 98 of the CFTR protein (p.Gln98Arg). This variant is present in population databases (rs397508464, gnomAD 0.006%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7581407, 16778407, 19652440). 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: 53606). 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: 29805046). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2017	Variant summary: The CFTR c.293A>G (p.Gln98Arg) variant involves the alteration of a conserved nucleotide located in the ABC transporter type 1, transmembrane domain of the protein (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/119728 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant has been reported in numerous CF patients with diverse ethnicity background including Caucasians, African Americans, and Asians. The variant in these patients present both homozygously and compound heterozygously. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Aug 21, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 14, 2023	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Mar 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 21, 2022	The p.Q98R pathogenic mutation (also known as c.293A>G), located in coding exon 4 of the CFTR gene, results from an A to G substitution at nucleotide position 293. The glutamine at codon 98 is replaced by arginine, an amino acid with highly similar properties. This mutation has been seen in individuals with elevated sweat chloride levels and pulmonary manifestations (Jung H et al. Korean J Lab Med, 2011 Jul;31:219-24). One study reported a homozygous individual with elevated sweat chloride levels and severe lung disease with allergic bronchopulmonary aspergillosis, but no gastrointestinal symptoms (Liu Y et al. Respirology, 2015 Feb;20:312-8). A functional study to assess the importance of the glutamine in this position suggests it may be involved in controlling the rate of chloride ion permeation through the pore (Ge N et al. J. Biol. Chem., 2004 Dec;279:55283-9). In addition, this mutation has been shown to decrease chloride channel activity compared to wild-type CFTR (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 25, 2022	The frequency of this variant in the general population, 0.000008 (2/251054 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in several compound heterozygotes affected with cystic fibrosis (UMD (http://www.umd.be/), PMIDs: 25580864 (2015), 23687349 (2013)). Additionally, functional studies showed reduced chloride channel activity indicating that this variant impacts protein function (PMID: 29805046 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 20, 2022	PP3, PM2, PM3_very_strong, PS3 -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 28, 2019

The CFTR c.293A>G; p.Gln98Arg variant (rs397508464) has been reported in multiple patients with cystic fibrosis (CF), either in trans to another pathogenic CFTR variant (Jung 2011, Koh 2005, Romey 1995) or in the homozygous state (Izumikawa 2009, Liu 2015). In testing performed at ARUP Laboratories, this variant has also been identified in multiple individuals with symptoms of CF who carry another pathogenic CFTR variant. Affected individuals with this variant can present with or without pancreatic insufficiency, although most are pancreatic-sufficient (CFTR2 database). The p.Gln98Arg variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 53606), and it is observed on only two chromosomes (2/251054 alleles) in the Genome Aggregation Database. The glutamine at residue 98 is highly conserved, it is located in the pore of the transmembrane channel of CFTR (Akabas 1994, Das 2017), and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Consistent with these predictions, the variant protein exhibits only 5.4% of wildtype chloride channel activity in a biochemical assay (Raraigh 2018). Based on available information, the p.Gln98Arg variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org/ Akabas M et al. Amino acid residues lining the chloride channel of the cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1994; 269(21):14865-8. Das J et al. Transmembrane helical interactions in the CFTR channel pore. PLoS Comput Biol. 2017; 13(6):e1005594. Izumikawa K et al. Unique mutations of the cystic fibrosis transmembrane conductance regulator gene of three cases of cystic fibrosis in Nagasaki, Japan. Intern Med. 2009; 48(15):1327-31. Jung H et al. Heterogeneous spectrum of CFTR gene mutations in Korean patients with cystic fibrosis. Korean J Lab Med. 2011; 31(3):219-24. Koh W et al. Report of a Korean patient with cystic fibrosis, carrying Q98R and Q220X mutations in the CFTR gene. J Korean Med Sci. 2006; 21(3):563-6. Liu Y et al. Characterization of gene mutations and phenotypes of cystic fibrosis in Chinese patients. Respirology. 2015; 20(2):312-8. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Romey M et al. Novel missense mutation in the first transmembrane segment of the CFTR gene (Q98R) identified in a male adult. Hum Mutat. 1995; 6(2):190-1. -

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

Pathogenic:1

Likely 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

CFTR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 01, 2021

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

.;D;.;.;T;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

.;M;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.0

D;N;.;.;N;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;.;.;D;.

Sift4G

Pathogenic

0.0

D;D;.;.;D;.

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.94

MutPred

0.94

.;Loss of catalytic residue at Q98 (P = 0.144);Loss of catalytic residue at Q98 (P = 0.144);Loss of catalytic residue at Q98 (P = 0.144);Loss of catalytic residue at Q98 (P = 0.144);Loss of catalytic residue at Q98 (P = 0.144);

MVP

1.0

MPC

0.013

ClinPred

0.99

GERP RS

5.7

Varity_R

0.84

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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