ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.293A>G (p.Gln98Arg) (rs397508464)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000588283 SCV000924242 pathogenic Cystic fibrosis 2017-12-08 reviewed by expert panel research
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000505966 SCV000603054 pathogenic not specified 2019-03-28 criteria provided, single submitter 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: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588283 SCV000696938 pathogenic Cystic fibrosis 2017-05-01 criteria provided, single submitter 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.
Counsyl RCV000588283 SCV000789400 likely pathogenic Cystic fibrosis 2017-02-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763149 SCV000893736 likely pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004424 SCV001163468 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000588283 SCV001169490 pathogenic Cystic fibrosis 2018-03-09 criteria provided, single submitter curation
Invitae RCV000588283 SCV001582765 pathogenic Cystic fibrosis 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 98 of the CFTR protein (p.Gln98Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs397508464, ExAC 0.02%). This variant has been observed in individuals with cystic fibrosis (PMID: 7581407, 16778407, 19652440). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53606). This variant has been reported to affect CFTR protein function (PMID: 29805046). For these reasons, this variant has been classified as Pathogenic.

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