ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1826A>G (p.His609Arg) (rs397508310)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000577469 SCV000924271 pathogenic Cystic fibrosis 2017-12-08 reviewed by expert panel research
Integrated Genetics/Laboratory Corporation of America RCV000577469 SCV000696876 pathogenic Cystic fibrosis 2017-02-28 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1826A>G (p.His609Arg) variant located in the P-loop containing nucleoside triphosphate hydrolase (via InterPro) causes a missense change involving a conserved nucleotide, which 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 119096 control chromosomes. Multiple publications cite the variant in affected individuals diagnosed with CF including both compound heterozygotes and 4 homozygous individuals, who are indicated to have a more severe phenotype than the compound heterozygous individuals. Although, no clinical diagnostic laboratories have cited this variant with a classification. In addition, LCA has classified additional missense variants surrounding the variant of interest in the pathogenic spectrum such as c.1837A>G (p.Ala613Thr VUS-possibly pathogenic), c.1841A>G (p.Asp614Gly pathogenic), and c.1853T>C (p.Ile618Thr VUS-possibly pathogenic), therefore, suggesting this region could be important for proper CFTR function. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001757 SCV001159373 likely pathogenic not specified 2018-07-29 criteria provided, single submitter clinical testing The CFTR c.1826A>G; p.His609Arg variant (rs397508310) has been reported in numerous individuals affected with cystic fibrosis, either in the homozygous state or in trans with another pathogenic variant (Keyeux 2003, McGinniss 2005, Moya-Quiles 2009, Ortiz 2017, Schrijver 2016, CFTR2 database). The variant is listed in ClinVar (Variation ID: 53398) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The histidine at residue 609 is moderately conserved, and computational algorithms (PolyPhen-2: damaging; SIFT: tolerated) predict conflicting effects of this variant on protein structure/function. Using a cell-based assay measuring CFTR-generated current, one study observed p.His609Arg variant activity at 2.2% of wildtype (Rareigh 2018). Based on available information, this variant is considered to be likely pathogenic. References: CFTR2 database: https://cftr2.org Keyeux G et al. CFTR mutations in patients from Colombia: implications for local and regional molecular diagnosis programs. Hum Mutat. 2003 Sep;22(3):259. McGinniss MJ et al. Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. Hum Genet. 2005 Dec;118(3-4):331-8. Moya-Quiles MR et al. CFTR H609R mutation in Ecuadorian patients with cystic fibrosis. J Cyst Fibros. 2009 Jul;8(4):280-1. Ortiz SC et al. Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation. Mol Genet Genomic Med. 2017 Nov;5(6):751-757. 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. Schrijver I et al. The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. J Mol Diagn. 2016 Jan;18(1):39-50.
CFTR-France RCV001009543 SCV001169638 pathogenic Cystic fibrosis; CFTR-related disorders 2018-03-09 criteria provided, single submitter curation the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577469 SCV000679342 not provided Cystic fibrosis no assertion provided literature only
Counsyl RCV000577469 SCV001132365 likely pathogenic Cystic fibrosis 2018-10-05 no assertion criteria provided clinical testing

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