ClinVar

Description

This variant is denoted STK11 c.527A>G at the cDNA level, p.Asp176Gly (D176G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAC>GGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However, a different missense variant involving a semi-conservative amino acid substitution at the same residue, Asp176Asn, has been observed in several patients and families with a clinical diagnosis of Peutz-Jeghers Syndrome (Mehenni 1998, de Leng 2007, Dai 2014, Wang 2014). Additionally, in vitro-based functional assays showed that STK11 Asp176Asn had no kinase activity and failed to induce G1 cell cycle arrest and p21 promoter transcription (Mehenni 1998, Nezu 1999, Tiainen 2002). STK11 Asp176Gly was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Asp176Gly occurs at a position that is conserved across species and is located in the substrate binding, phospho transfer initiation, and protein kinase domains (Hearle 2006, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider STK11 Asn176Gly to be a likely pathogenic variant.