ClinVar Miner

Submissions for variant NM_030662.3(MAP2K2):c.818A>G (p.Lys273Arg) (rs539555837)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000522446 SCV000616571 likely benign Rasopathy 2017-05-09 reviewed by expert panel curation The filtering allele frequency of the c.818A>G (p.Lys273Arg) variant in the MAP2K2 gene is 0.0368% (6/7088) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)
GeneDx RCV000158027 SCV000207962 likely benign not provided 2018-01-23 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781517 SCV000919610 likely benign not specified 2018-04-02 criteria provided, single submitter clinical testing Variant summary: MAP2K2 c.818A>G (p.Lys273Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 263682 control chromosomes (gnomAD). The observed variant frequency is approximately 27-fold above the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06). In addition, the variant is most prevalent in the Latino subpopulation in gnomAD (3.3e-04), which is approximately 132-fold above the maximal expected allele frequency, strongly suggesting that the variant is benign. The c.818A>G has been reported in the literature in one individual affected with Cardiofaciocutaneous Syndrome. These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, where studies in zebrafish development showed a phenotype, different from wt, in approximately 2/3rds of K273R embryos analyzed (Anastasaki_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000990136 SCV001140954 likely benign Cardiofaciocutaneous syndrome 4 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000522446 SCV001233396 uncertain significance Rasopathy 2019-12-01 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 273 of the MAP2K2 protein (p.Lys273Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs539555837, ExAC 0.08%). This variant has been observed in an individual affected with cardio-facio-cutaneous syndrome (PMID: 17366577). ClinVar contains an entry for this variant (Variation ID: 40824). This variant has been reported to affect MAP2K2 protein function (PMID: 19376813). 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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