ClinVar Miner

Submissions for variant NM_030662.3(MAP2K2):c.842G>A (p.Arg281Gln) (rs1332074575)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000690261 SCV001335326 uncertain significance Rasopathy 2020-03-19 reviewed by expert panel curation The c.842G>A (p.Arg281Gln) variant in MAP2K2 was present in 0.007324% (1/13654) of Latino chromosomes in gnomAD v3. It was observed in one healthy adult male who did not have features of a RASopathy (BS2 not met; Baylor internal data). 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 variants are common (PP2; PMID: 29493581). Computational analysis and splice site predictors suggest that this variant does not impact the protein (BP4). In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PP2, BP4.
Invitae RCV000690261 SCV000817942 uncertain significance Rasopathy 2018-02-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 281 of the MAP2K2 protein (p.Arg281Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with 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 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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