ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1226G>A (p.Arg409Gln) (rs587782364)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131326 SCV000186299 likely benign Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Structural Evidence,Other data supporting benign classification
Invitae RCV000197480 SCV000254544 uncertain significance Peutz-Jeghers syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 409 of the STK11 protein (p.Arg409Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587782364, ExAC 0.005%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 142292). 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.
Counsyl RCV000197480 SCV000488336 uncertain significance Peutz-Jeghers syndrome 2016-03-01 criteria provided, single submitter clinical testing
GeneDx RCV000657038 SCV000567098 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1226G>A at the cDNA level, p.Arg409Gln (R409Q) 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 literature as pathogenic or benign. STK11 Arg409Gln was not observed in large population cohorts (Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. STK11 Arg409Gln is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether STK11 Arg409Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000487216 SCV000602212 uncertain significance not specified 2017-06-13 criteria provided, single submitter clinical testing
Color RCV000131326 SCV000686606 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000487216 SCV000731470 uncertain significance not specified 2017-04-21 criteria provided, single submitter clinical testing The p.Arg409Gln variant in STK11 has not been previously reported in the literat ure in individuals with Peutz-Jeghers syndrome, but has been reported in ClinVar (Variation ID 142292). This variant has also been identified in 6/80576 of Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs587782364). Computational prediction tools and conservati on analysis suggest that the p.Arg409Gln variant may not impact the protein, tho ugh this information is not predictive enough to rule out pathogenicity. In summ ary, the clinical significance of the p.Arg409Gln variant is uncertain.
PreventionGenetics,PreventionGenetics RCV000657038 SCV000806072 uncertain significance not provided 2018-01-09 criteria provided, single submitter clinical testing

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