ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.650A>G (p.Glu217Gly) (rs121909046)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000007660 SCV000267252 uncertain significance Cystic fibrosis 2016-03-18 criteria provided, single submitter reference population
Illumina Clinical Services Laboratory,Illumina RCV001095295 SCV000466505 likely benign CFTR-related disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000007660 SCV000562306 benign Cystic fibrosis 2020-12-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506350 SCV000601129 uncertain significance not specified 2017-01-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000506350 SCV000697040 uncertain significance not specified 2020-09-24 criteria provided, single submitter clinical testing Variant summary: CFTR c.650A>G (p.Glu217Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0044 in 252904 control chromosomes, predominantly at a frequency of 0.0095 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing CFTR-related diseases phenotype (0.013), suggesting that the variant may be a benign polymorphism found in this subpopulation. The variant, c.650A>G, has been reported in the literature in individuals affected with Cystic Fibrosis (CF), chronic pancreatitis, and CBAVD (example: Lee_2003, Audrezet_EJHG_2002, Li_2012) but also in many controls. These reports do not provide unequivocal conclusions about association of the variant with CFTR or CFTR-Related Diseases., since most of them did not mention testing patients for genomic rearrangements and do not provide a complete genotype. Munck et al report a patient with inconclusive CF diagnosis harboring the variant of interest and F508del that has sweat chloride levels < 30 mmol/L (Munck _2019). CFTR-France database also reports this variant in two asymptomatic compound heterozygotes with a CF-causing variant in trans. Functional studies report significantly decreased chloride channel activity associated with the variant when transfected into CHO-K1 and BHK cells (Lee_2003, Hammerl_2001, Chang_2018). Seven other ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=3) or uncertain significance (n=4). Taken together, the control data are in conflict with the functional data, and there are no co-segregation studies to determine its causal role. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000586415 SCV000700761 uncertain significance not provided 2018-07-10 criteria provided, single submitter clinical testing
Mendelics RCV000007660 SCV001137468 uncertain significance Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001025354 SCV001187527 benign Inborn genetic diseases 2018-03-02 criteria provided, single submitter clinical testing General population or sub-population frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign)
Nilou-Genome Lab RCV000007660 SCV001737307 uncertain significance Cystic fibrosis 2021-06-10 criteria provided, single submitter clinical testing
OMIM RCV000007660 SCV000027861 pathogenic Cystic fibrosis 2003-09-15 no assertion criteria provided literature only
Natera, Inc. RCV000007660 SCV001453952 uncertain significance Cystic fibrosis 2017-06-13 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000586415 SCV001743728 likely benign not provided no assertion criteria provided clinical testing

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