19-4110558-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PS3_SupportingPM2_SupportingPM1PS4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.401A>G variant in the MAP2K2 gene is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 134 (p.Tyr134Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.966, predicting a damaging impact on protein function (PP3). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 (PM1, AA 128-138). This variant has been identified in at least 4 patients with RASopathy (PS4_Moderate; PMID:18413255, 18039235, 21062266, 23885229). ERK phosphorylation assays showed that this variant led to increased phosphorylation compared to wild-type (PS3_Supporting; PMID:17981815, 18413255). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PS3_Supporting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA180890/MONDO:0021060/048
Frequency
Consequence
NM_030662.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MAP2K2 | ENST00000262948.10 | c.401A>G | p.Tyr134Cys | missense_variant | Exon 3 of 11 | 1 | NM_030662.4 | ENSP00000262948.4 | ||
MAP2K2 | ENST00000394867.9 | n.840A>G | non_coding_transcript_exon_variant | Exon 2 of 10 | 5 | |||||
MAP2K2 | ENST00000599345.1 | n.598A>G | non_coding_transcript_exon_variant | Exon 3 of 7 | 5 | |||||
MAP2K2 | ENST00000687128.1 | n.840A>G | non_coding_transcript_exon_variant | Exon 2 of 7 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461718Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727154
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cardio-facio-cutaneous syndrome Pathogenic:1Other:1
The c.401A>G (p.Tyr134Cys) variant in MAP2K2 has been identified in one patient with clinical features of a RASopathy (PMID 18413255). In vitro functional studies provide some evidence that the p.Tyr134Cys variant may impact protein function (PS3; PMID 18413255). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr134Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PM2, PM1, PP2, PP3. -
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Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Noonan syndrome 1 Pathogenic:1
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not provided Pathogenic:1
Published functional studies demonstrate a damaging effect in which the variant causes increased kinase activity and activation of downstream effectors (MEK and ERK), indicating a gain of function (Rodriguez-Viciana et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); 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 (HGMD); This variant is associated with the following publications: (PMID: 24803665, 29752777, 25370473, 22753777, 19156172, 26399658, 22177953, 29493581, 18042262, 18413255) -
RASopathy Pathogenic:1
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 134 of the MAP2K2 protein (p.Tyr134Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cardio-facio-cutaneous syndrome (PMID: 18039235, 18413255, 23885229). This variant is also known as MEK2 Y134C. ClinVar contains an entry for this variant (Variation ID: 177868). 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%. Experimental studies have shown that this missense change affects MAP2K2 function (PMID: 17981815, 18413255, 19376813). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at