ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.221G>A (p.Arg74Gln) (rs142540482)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046556 SCV000074569 uncertain significance Cystic fibrosis 2019-05-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 74 of the CFTR protein (p.Arg74Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs142540482, ExAC 0.03%). This variant has been reported in several individuals affected with chronic pancreatitis (PMID: 25033378, 17003641, 22427236, 21520337), but has not been reported in individuals with cystic fibrosis. ClinVar contains an entry for this variant (Variation ID: 53456) Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000589418 SCV000228894 uncertain significance not provided 2017-07-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000177074 SCV000602983 uncertain significance not specified 2016-12-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000177074 SCV000696890 uncertain significance not specified 2020-11-23 criteria provided, single submitter clinical testing Variant summary: CFTR c.221G>A (p.Arg74Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. One publication (Ramalho_2015) and 2/4 computational tools predict that the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies.The variant allele was found at a frequency of 0.00026 in 254510 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (0.00026 vs 0.0063), allowing no conclusion about variant significance. The variant was reported in one patient with a CFTR-related disorder (unspecified phenotype) however, this patient also carried a pathogenic CFTR variant (c.3846G>A (p.W1282X)) in cis, supporting a benign role for the variant of interest in this case (Trujillano_2013). On the other hand, multiple publications cite the variant in individuals with pancreatitis (e.g. LaRusch_2014, Keiles_2006, Masson_2013, Rosendahl_2012, Steiner_2011). In several patients, the variant was reported along with R297Q (without specifying the phase), and this co-occurring variant (i.e. c.890G>A ;p.Arg297Gln), was also reported in several patients with idiopathic pancreatitis. Additionally the variant was found to be associated with pancreatitis in a case control study, when patients also have the SPINK1 pathogenic mutation p.N34S (LaRusch_2014). This study also reported experimental evidence that the variant, p.Arg74Gln, results in significantly reduced bicarbonate channel function (LaRusch_2014). Authors of this study concluded that variants that impair bicarbonate permeation may increase the risk for pancreatitis, but not for cystic fibrosis. Another functional study has reported that the variant impairs the association of CFTR with WNK1, reducing WNK1-mediated regulcation of HCO3- channel activity (Kim_2019). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Counsyl RCV000046556 SCV000794964 uncertain significance Cystic fibrosis 2017-10-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV001014832 SCV001175594 uncertain significance Inborn genetic diseases 2020-09-02 criteria provided, single submitter clinical testing The p.R74Q variant (also known as c.221G>A), located in coding exon 3 of the CFTR gene, results from a G to A substitution at nucleotide position 221. The arginine at codon 74 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in an individual with idiopathic chronic pancreatitis who was negative for mutations in the PRSS1 gene (Rosendahl J et al. Pancreatology, 2010 May;10:165-72). Functional studies found that this variant did not affect chloride current density, but significantly reduced bicarbonate permeability and conductance in HEK 293T cells, which may increase the risk of pancreatitis (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376; Kim Y et al. Cell Mol Gastroenterol Hepatol, 2020 Sep;9:79-103)<span style="background-color:initial">. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence, this variant is unlikely to be causative of classic CF, however its clinical contribution to the development of a CFTR-related disorder is uncertain.​
Illumina Clinical Services Laboratory,Illumina RCV001161752 SCV001323653 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000589418 SCV001714826 uncertain significance not provided 2019-05-07 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000046556 SCV001821986 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000046556 SCV001453944 uncertain significance Cystic fibrosis 2018-05-25 no assertion criteria provided clinical testing

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