7-117530918-A-G

Variant names:

• chr7-117530918-A-G
• rs397508464
• NM_000492.4:c.293A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PP2 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
• Publications: 33 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000492.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• 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 VariationId is 53606.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.293A>G	p.Gln98Arg	missense	Exon 4 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.293A>G	p.Gln98Arg	missense	Exon 4 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.293A>G	p.Gln98Arg	missense	Exon 4 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.293A>G	p.Gln98Arg	missense	Exon 4 of 26	ENSP00000389119.1

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

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251054 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.0000896 AC: 4 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111166

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41466

American (AMR) AF: 0.0000656 AC: 1 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000252 Hom.: 0

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

Feb 01, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Apr 14, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

Mar 09, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Dec 08, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

May 01, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 21, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 21, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Pathogenic:2

Apr 20, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PM3_very_strong, PS3

Jun 25, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 28, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

CFTR-related disorder Pathogenic:1

Jan 01, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.94		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
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397508464; hg19: chr7-117170972;