ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1517T>C (rs397508224)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046330 SCV000074343 uncertain significance Cystic fibrosis 2016-11-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 506 of the CFTR protein (p.Ile506Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs397508224, ExAC 0.009%). This variant has been reported to be homozygous in one Iranian individual with cystic fibrosis (CF) (PMID: 16436643). In addition, this variant has been observed in several CF populations, mostly from southern Europe, with an allele frequency of ~0.05% (7/13786 chromosomes) (PMID: 15698946, 10798368, 10923036, 16963320, 21184098). While this frequency is higher than observed in the general population, the statistical significance of this observation has not been tested. 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 disruptive, but these predictions have not been confirmed by published functional studies. Multiple different missense substitutions at this codon (p.Ile506Met, p.Ile506Ser, p.Ile506Leu) have been reported in individuals with disease (PMID: 7509683, 7525963, 11788090), but the clinical significance of these variants is currently uncertain. Until this certainty can be resolved, this observation should not be used to inform the interpretation of other rare missense change at this position. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000046330 SCV000798816 uncertain significance Cystic fibrosis 2018-03-26 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727671 SCV000854981 likely pathogenic not provided 2018-07-30 criteria provided, single submitter clinical testing
CFTR-France RCV000046330 SCV001169473 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000727671 SCV001450135 pathogenic not provided 2015-05-29 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000046330 SCV001573142 likely pathogenic Cystic fibrosis 2021-04-29 criteria provided, single submitter clinical testing

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