NM_000492.4(CFTR):c.293A>G (p.Gln98Arg) AND Cystic fibrosis

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Dec 8, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000588283.13

Allele description [Variation Report for NM_000492.4(CFTR):c.293A>G (p.Gln98Arg)]

NM_000492.4(CFTR):c.293A>G (p.Gln98Arg)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.293A>G (p.Gln98Arg)

HGVS:

NC_000007.14:g.117530918A>G
NG_016465.4:g.70135A>G
NM_000492.4:c.293A>GMANE SELECT
NP_000483.3:p.Gln98Arg
NP_000483.3:p.Gln98Arg
LRG_663t1:c.293A>G
LRG_663:g.70135A>G
LRG_663p1:p.Gln98Arg
NC_000007.13:g.117170972A>G
NM_000492.3:c.293A>G
P13569:p.Gln98Arg

Protein change:

Q98R

Links:

UniProtKB: P13569#VAR_000116; dbSNP: rs397508464

NCBI 1000 Genomes Browser:

rs397508464

Molecular consequence:

NM_000492.4:c.293A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696938	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 1, 2017)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 23687349, 9150159, 10923036, 15300780, 17331079, 19652440, 7581407, 15858154, 15365999, 25580864, 15698946, 16778407, 21779199 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000789400	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Feb 1, 2017)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19652440, 7581407, 23687349, 21779199, 25580864, 15365999 Citation Link,
SCV000924242	CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Dec 8, 2017)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001169490	CFTR-France	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	Pathogenic (Mar 9, 2018)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV001582765	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7581407, 16778407, 19652440, 29805046, 28492532
SCV002583283	Baylor Genetics	no assertion criteria provided	Pathogenic (Aug 21, 2021)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7581407, 18456578, 19652440, 16778407, 29805046
SCV002747817	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 21, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15504721, 21779199, 25580864, 29805046 Citation Link,
SCV003927219	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research, curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.

Macek M Jr, Mackova A, Hamosh A, Hilman BC, Selden RF, Lucotte G, Friedman KJ, Knowles MR, Rosenstein BJ, Cutting GR.

Am J Hum Genet. 1997 May;60(5):1122-7.

PubMed [citation]

PMID:: 9150159
PMCID:: PMC1712417

Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France.

Claustres M, Guittard C, Bozon D, Chevalier F, Verlingue C, Ferec C, Girodon E, Cazeneuve C, Bienvenu T, Lalau G, Dumur V, Feldmann D, Bieth E, Blayau M, Clavel C, Creveaux I, Malinge MC, Monnier N, Malzac P, Mittre H, Chomel JC, Bonnefont JP, et al.

Hum Mutat. 2000;16(2):143-56.

PubMed [citation]

PMID:: 10923036

See all PubMed Citations (20)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696938.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000789400.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR2, SCV000924242.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR-France, SCV001169490.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001582765.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV002583283.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002747817.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV003927219.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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