ClinVar Miner

Submissions for variant NM_030662.3(MAP2K2):c.692G>T (p.Arg231Leu) (rs730880511)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788004 SCV000927036 uncertain significance Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.692G>T (p.Arg231Leu) variant has been identified in at least 2 independent occurrences in patients with clinical features of RASopathies (PS4_Supporting GeneDx, Invitae internal data, GTR Lab IDs 26957, 500031; ClinVar SCV000207960.9, SCV000551455.2). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg231Leu variant may impact the protein (PP3).In summary, the clinical significance of the p.Arg231Leu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PP2, PP3.
GeneDx RCV000158025 SCV000207960 likely pathogenic not provided 2014-09-08 criteria provided, single submitter clinical testing A variant of unknown significance has been identified. The R231L missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R231L amino acid substitution is non-conservative with a positively-charged residue (Arg) being replaced by a neutral, non-polar residue (Leu). The position at which this substitution occurs is conserved in mammals and through vertebrates. The NHLBI ESP Exome Variant Server reports that R231L was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Another missense change at this codon, R231C, has been seen previously at GeneDx in a proband and parent. However, clinical information for the parent was not provided. Therefore, the R231L missense change is a strong candidate for a disease-causing mutation, although the possibility that it is a benign polymorphism cannot be completely excluded. The variant is found in NOONAN panel(s).
Invitae RCV000466246 SCV000551455 uncertain significance Rasopathy 2016-04-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 231 of the MAP2K2 protein (p.Arg231Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MAP2K2-related disease. ClinVar contains an entry for this variant (Variation ID: 40818). 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. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000824948 SCV000965983 uncertain significance Noonan syndrome with multiple lentigines no assertion criteria provided clinical testing

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.