ClinVar Miner

Submissions for variant NM_030662.3(MAP2K2):c.856G>A (p.Gly286Arg) (rs730880523)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158048 SCV000207983 uncertain significance not provided 2012-02-03 criteria provided, single submitter clinical testing This variant is denoted c.856 G>A at the cDNA level or p.Gly286Arg (G286R) at the protein level. The G286R missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G286R missense change is a non-conservative substitution with a neutral and non-polar residue (Gly) being replaced by a positively charged and polar residue (Arg). The NHLBI ESP Exome Variant Server reports that Arginine 286 was not observed in approximately 5000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, this variant occurs at a position that is only moderately conserved in the protein and not conserved in related proteins. Although the majority of missense variants in MAP2K2 are pathogenic, no disease-causing mutation has been reported after codon 273. The variant is found in NOONAN panel(s).
Invitae RCV000654943 SCV000776851 uncertain significance Rasopathy 2017-10-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 286 of the MAP2K2 protein (p.Gly286Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs730880523, ExAC 0.01%). This variant has not been reported in the literature in individuals with MAP2K2-related disease. ClinVar contains an entry for this variant (Variation ID: 40829). 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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