ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.950A>C (p.Glu317Ala) (rs730881988)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161011 SCV000211722 uncertain significance not provided 2015-03-13 criteria provided, single submitter clinical testing This variant is denoted STK11 c.950A>C at the cDNA level, p.Glu317Ala (E317A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Glu317Ala 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 Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Glu317Ala occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 Glu317Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574139 SCV000672330 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000701488 SCV000830291 uncertain significance Peutz-Jeghers syndrome 2018-07-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 317 of the STK11 protein (p.Glu317Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. 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: 182916). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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