ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2153C>G (p.Pro718Arg)

gnomAD frequency: 0.00011  dbSNP: rs142432539
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001785766 SCV001175335 uncertain significance Cystic fibrosis 2021-11-30 criteria provided, single submitter clinical testing The p.P718R variant (also known as c.2153C>G), located in coding exon 14 of the CFTR gene, results from a C to G substitution at nucleotide position 2153. The proline at codon 718 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in a newborn with an abnormal newborn screening result in conjunction with p.F508del; however, further clinical information and phase was not provided (Prach L et al. J Mol Diagn, 2013 Sep;15:710-22). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193706 SCV001362741 uncertain significance not specified 2023-03-14 criteria provided, single submitter clinical testing Variant summary: CFTR c.2153C>G (p.Pro718Arg) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251228 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2153C>G has been reported in the literature in two newborns by two different studies (example, Ratkiewicz_2017, Prach_2013) without adequate or conclusive information, however, in relation to pathogenicity. These report(s) do not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk/Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 uncertain significance.
Genome-Nilou Lab RCV001785766 SCV002027440 uncertain significance Cystic fibrosis 2021-09-05 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002497338 SCV002814374 uncertain significance Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2021-07-21 criteria provided, single submitter clinical testing
Invitae RCV001785766 SCV003785321 uncertain significance Cystic fibrosis 2022-02-17 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 718 of the CFTR protein (p.Pro718Arg). This variant is present in population databases (rs142432539, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 820807). 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003478621 SCV004221670 uncertain significance not provided 2022-09-15 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.00043 (7/16236 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in children identified in newborn screening studies who also carried other CFTR variants (PMID: 23810505 (2013), 28194692 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc. RCV001832337 SCV002080714 uncertain significance CFTR-related disorders 2018-07-28 no assertion criteria provided clinical testing

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