ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.911G>A (p.Arg304Gln) (rs376280361)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569076 SCV000672332 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-10 criteria provided, single submitter clinical testing
GeneDx RCV000479636 SCV000567199 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing This variant is denoted STK11 c.911G>A at the cDNA level, p.Arg304Gln (R304Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the germline literature as pathogenic or benign. STK11 Arg304Gln was not observed in large population cohorts (Lek 2016). This variant is located in the XI kinase domain (Hearle 2006, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether STK11 Arg304Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000536973 SCV000629157 uncertain significance Peutz-Jeghers syndrome 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 304 of the STK11 protein (p.Arg304Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs376280361, ExAC 0.009%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 419419). 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. A different missense substitution at this codon (p.Arg304Trp) has been determined to be pathogenic (PMID: 12552571, 10441497, 9809980, 17404884, 15121768, 12865922). This suggests that the arginine residue is critical for STK11 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Mendelics RCV000536973 SCV000839420 uncertain significance Peutz-Jeghers syndrome 2018-07-02 criteria provided, single submitter clinical testing

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