ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1274G>A (p.Arg425His) (rs730881992)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213041 SCV000211730 uncertain significance not provided 2016-03-03 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1274G>A at the cDNA level, p.Arg425His (R425H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign; however, it was identified in a leukemia cell line (Kalender Atak 2012). STK11 Arg425His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. STK11 Arg425His occurs at a position that is conserved across species and is located in the c-terminal domain (Hearle 2006). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether STK11 Arg425His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000161015 SCV000213892 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000195803 SCV000254546 uncertain significance Peutz-Jeghers syndrome 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 425 of the STK11 protein (p.Arg425His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 182920). 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 disruptive, 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.
Color RCV000161015 SCV000686612 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing

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