ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.440G>A (p.Arg147His) (rs587780717)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123060 SCV000166355 uncertain significance Peutz-Jeghers syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 147 of the STK11 protein (p.Arg147His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587780717, ExAC 0.06%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 135921). 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.
GeneDx RCV000216877 SCV000279177 uncertain significance not provided 2017-04-28 criteria provided, single submitter clinical testing This variant is denoted STK11 c.440G>A at the cDNA level, p.Arg147His (R147H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Arg147His was observed at an allele frequency of 0.059% (2/3370) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. STK11 Arg147His occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the protein kinase domain and within the site of catalysis (Hearle 2006) In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether STK11 Arg147His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000565548 SCV000664311 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000565548 SCV000686648 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing

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