ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1429C>T (p.Pro477Ser) (rs139054556)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532369 SCV000625726 uncertain significance Cystic fibrosis 2017-04-01 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 477 of the CFTR protein (p.Pro477Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs139054556, ExAC 0.02%) but has not been reported in the literature in individuals with a CFTR-related disease. 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759753 SCV000889285 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781249 SCV000919157 uncertain significance not specified 2018-03-13 criteria provided, single submitter clinical testing Variant summary: CFTR c.1429C>T (p.Pro477Ser) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 276996 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (4e-05 vs 0.0063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1429C>T in affected individuals and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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