ClinVar Miner

Submissions for variant NM_030662.3(MAP2K2):c.834C>G (p.Ile278Met) (rs766540227)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413176 SCV000491002 uncertain significance not specified 2015-05-26 criteria provided, single submitter clinical testing The I278M variant has not been published as a pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It 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. The I278M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species. However, a missense variant in a nearby residue (K273R) has been reported in the Human Gene Mutation Database in association with Cardio-Facio-Cutaneous (CFC) syndrome (Stenson et al., 2009), and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000458371 SCV000551457 uncertain significance Rasopathy 2016-09-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 278 of the MAP2K2 protein (p.Ile278Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. 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. 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. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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