ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.846A>T (p.Glu282Asp) (rs142864834)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506367 SCV000602997 uncertain significance not specified 2016-11-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726823 SCV000703305 uncertain significance not provided 2018-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000506367 SCV000052198 uncertain significance not specified 2019-05-30 criteria provided, single submitter clinical testing CFTR c.846A>T (p.Glu282Asp) results in a 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 4.8e-05 in 249426 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (4.8e-05 vs 0.013), allowing no conclusion about variant significance. c.846A>T has been reported in the literature in an individual without specific phenotypic information provided, from a cohort of elderly Brazilians (Naslavsky_2017). This report does not allow any conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000796154 SCV000935652 uncertain significance Cystic fibrosis 2018-10-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 282 of the CFTR protein (p.Glu282Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs142864834, ExAC 0.06%). This variant has not been reported in the literature in individuals with CFTR-related disease. ClinVar contains an entry for this variant (Variation ID: 35891). 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. 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.

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