ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.910C>T (p.Arg304Trp) (rs786201090)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162596 SCV000213014 likely pathogenic Inborn genetic diseases 2016-07-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
GeneDx RCV000256082 SCV000322048 pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing This pathogenic variant is denoted STK11 c.910C>T at the cDNA level, p.Arg304Trp (R304W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been observed in multiple individuals with Peutz-Jeghers syndrome (PJS) (Resta 1998, Lim 2003, Amos 2004, Schumacher 2005, Hearle 2006, Salloch 2010). In vitro studies found that this variant causes abnormal cellular localization, aberrant phosphorylation patterns, and loss of kinase activity (Nezu 1999, Boudeau 2003). STK11 Arg304Trp was not observed in large population cohorts (Lek 2016). STK11 Arg304Trp is located in the protein kinase domain (UniProt). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000435642 SCV000541172 pathogenic Peutz-Jeghers syndrome 2016-08-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 304 of the STK11 protein (p.Arg304Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs786201090, ExAC no frequency). This variant has been reported in individuals affected with Peutz-Jeghers syndrome (PMID: 9809980, 17404884, 15121768, 12865922). ClinVar contains an entry for this variant (Variation ID: 183802). Experimental studies have shown that this missense change abolishes STK11 kinase activity in vitro (PMID: 12552571, 10441497). A different missense substitution at this codon (p.Arg304Pro) has been determined to be pathogenic (PMID: 16287113). This suggests that the arginine residue is critical for STK11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000435642 SCV000918283 pathogenic Peutz-Jeghers syndrome 2017-10-26 criteria provided, single submitter clinical testing Variant summary: The STK11 c.910C>T (p.Arg304Trp) variant located in the protein kinase domain involves the alteration of a non-conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 30938 control chromosomes (gnomAD). Multiple publications have cited the variant in PJS patients. In addition, multiple functional studies, Boudeau_2003 and Nezu_1999, found the variant to cause abnormal cellular localization, aberrant phosphorylation patterns, and loss of kinase activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Database of Curated Mutations (DoCM) RCV000435642 SCV000510520 likely pathogenic Peutz-Jeghers syndrome 2016-05-13 no assertion criteria provided literature only

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