7-117530918-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q98P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 8.87

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 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain 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	UniProt
CFTR	NM_000492.4	c.293A>G	p.Gln98Arg	missense_variant	4/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.293A>G	p.Gln98Arg	missense_variant	4/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32

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: 2 AN: 251054 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135670

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: 4 AN: 1460552 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726676

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: 2 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

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: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:8

Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, criteria provided, single submitter	curation	CFTR-France	Mar 09, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Aug 21, 2021	- -
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	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 01, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 20, 2022	PP3, PM2, PM3_very_strong, PS3 -
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. -

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

Sep 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
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	D
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

Other links and lift over

dbSNP: rs397508464; hg19: chr7-117170972;