ClinVar Miner

Submissions for variant NM_030662.4(MAP2K2):c.281C>T (p.Ser94Leu)

gnomAD frequency: 0.00005  dbSNP: rs202220799
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000521587 SCV000616542 uncertain significance RASopathy 2017-05-09 reviewed by expert panel curation The c.281C>T (p.Ser94Leu) variant in MAP2K2 has been identified in 2 independent occurrences in patients with a RASopathy (PS4 not met; GeneDx, LMM internal data; GTR ID; 26957, 21766; SCV000204231.4; SCV000207977.8). 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). In summary, the clinical significance of the p.Ser94Leu variant is uncertain. ACMG/AMP criteria applied: PP2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154558 SCV000204231 likely benign not specified 2016-05-27 criteria provided, single submitter clinical testing p.Ser94Leu in exon 2 of MAP2K2: This variant is not expected to have clinical s ignificance because it has been identified in two unaffected Caucasian parents. It has also been identified in 3/10138 of African chromosomes and 2/11476 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs202220799).
GeneDx RCV000767152 SCV000207977 uncertain significance not provided 2020-08-12 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance by the ClinGen RASopathy Variant Curation Expert Panel (SCV000616542.3; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014)
Labcorp Genetics (formerly Invitae), Labcorp RCV000521587 SCV000659161 uncertain significance RASopathy 2025-01-27 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 94 of the MAP2K2 protein (p.Ser94Leu). This variant is present in population databases (rs202220799, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. ClinVar contains an entry for this variant (Variation ID: 40786). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MAP2K2 function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154558 SCV001362364 likely benign not specified 2025-02-10 criteria provided, single submitter clinical testing Variant summary: MAP2K2 c.281C>T (p.Ser94Leu) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 282136 control chromosomes. The observed variant frequency is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome And Related Conditions phenotype (2.5e-06). To our knowledge, no occurrence of c.281C>T in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 40786). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity RCV003129758 SCV003808260 uncertain significance Cardiofaciocutaneous syndrome 4 2019-06-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV004991982 SCV005616826 uncertain significance Cardiovascular phenotype 2024-09-27 criteria provided, single submitter clinical testing The p.S94L variant (also known as c.281C>T), located in coding exon 2 of the MAP2K2 gene, results from a C to T substitution at nucleotide position 281. The serine at codon 94 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics RCV003129758 SCV005648279 likely benign Cardiofaciocutaneous syndrome 4 2024-06-18 criteria provided, single submitter clinical testing

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