ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.827A>G (p.Lys276Arg) (rs777603059)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413183 SCV000490985 likely pathogenic not provided 2015-04-23 criteria provided, single submitter clinical testing The K276R variant in the PTPN11 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The K276R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K276R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs within the Tyrosine-protein phosphatase domain in a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The K276R variant is a strong candidate for a disease-causing variant However, the possibility it may be a rare benign variant cannot be excluded.
Integrated Genetics/Laboratory Corporation of America RCV000781774 SCV000920092 uncertain significance not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.827A>G (p.Lys276Arg) results in a conservative amino acid change located in the catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.827A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.