ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1150C>T (p.Arg384Trp) (rs752015385)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218896 SCV000279188 uncertain significance not provided 2017-02-06 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1150C>T at the cDNA level, p.Arg384Trp (R384W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Arg384Trp 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 Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Arg384Trp occurs at a position that is not conserved across species and is not located in a known functional domain (Hearle 2006, 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 Arg384Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000231028 SCV000284845 uncertain significance Peutz-Jeghers syndrome 2020-08-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 384 of the STK11 protein (p.Arg384Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs752015385, ExAC 0.004%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 234419). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The tryptophan amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV000572898 SCV000664318 likely benign Hereditary cancer-predisposing syndrome 2020-09-02 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Counsyl RCV000231028 SCV000785241 uncertain significance Peutz-Jeghers syndrome 2017-06-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000572898 SCV000903158 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-17 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000572898 SCV000886718 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-04 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356885 SCV001552167 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The STK11 p.Arg384Trp variant was identified in the literature although a frequency in an affected population was not provided (Cheng 2015). The variant was also identified in dbSNP as “with Uncertain significance allele”. The variant was not identified in ClinVar or LOVD 3.0. The variant was identified in control databases in 1 of 30920 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 1 of 8702 chromosomes (freq: 0.0001), while the variant was not observed in the European, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg384 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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