Submissions for variant NM_000455.5(STK11):c.125G>A (p.Arg42Gln)

dbSNP: rs148830698

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000220188	SCV000279705	uncertain significance	not provided	2015-12-16	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.125G>A at the cDNA level, p.Arg42Gln (R42Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Arg42Gln was observed with an allele frequency of 0.1% in the European populations in 1000 Genomes. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. STK11 Arg42Gln occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is not located in a known functional domain (Hearle 2006). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether STK11 Arg42Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001010594	SCV001170818	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-24	criteria provided, single submitter	clinical testing	The p.R42Q variant (also known as c.125G>A), located in coding exon 1 of the STK11 gene, results from a G to A substitution at nucleotide position 125. The arginine at codon 42 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV001297981	SCV001487021	uncertain significance	Peutz-Jeghers syndrome	2022-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 42 of the STK11 protein (p.Arg42Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 234700). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Genome-Nilou Lab	RCV001297981	SCV002057745	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469111	SCV004205544	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2023-10-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001010594	SCV004362378	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 42 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.