rs121434499

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PM1PS3_SupportingPP3PM2_SupportingPM6_Strong

This summary comes from the ClinGen Evidence Repository: The c.400T>C variant in the MAP2K2 gene is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 134 (p.Tyr134His). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.917, 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). Furthermore, a different pathogenic variant at this residue (Tyr134Cys) has been identified in several patients with RASopathies (PM5). This variant has been identified in at least 6 patients with a RASopathy, of which 2 were unconfirmed de novo cases (PS4, PM6_Strong; Partners LMM, Labcorp internal data, ClinVar: SCV000063166.5, SCV002210187.3; PMID:18042262, 18456719, 27763634). Western blot assay in Ba/F3 cells showed that the variant activated ERK signaling while the wildtype did not (PS3_Supporting, PMID:30867592). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4, PM6_Strong, PM1, PM5, PS3_Supprting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA119417/MONDO:0021060/048

Frequency

Genomes: not found (cov: 32)

Consequence

MAP2K2
NM_030662.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 9.10

Variant links:

Genes affected

MAP2K2 (HGNC:6842): (mitogen-activated protein kinase kinase 2) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK2/ERK3. The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome), a disease characterized by heart defects, cognitive disability, and distinctive facial features similar to those found in Noonan syndrome. The inhibition or degradation of this kinase is also found to be involved in the pathogenesis of Yersinia and anthrax. A pseudogene, which is located on chromosome 7, has been identified for this gene. [provided by RefSeq, Jul 2008]

MAP2K2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM6

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4 link	c.400T>C	p.Tyr134His	missense_variant	Exon 3 of 11	ENST00000262948.10	NP_109587.1	P36507
MAP2K2	XM_006722799.3 link	c.400T>C	p.Tyr134His	missense_variant	Exon 3 of 9		XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAP2K2	ENST00000262948.10 link	c.400T>C	p.Tyr134His	missense_variant	Exon 3 of 11	1	NM_030662.4	ENSP00000262948.4	P36507
MAP2K2	ENST00000394867.9 link	n.839T>C		non_coding_transcript_exon_variant	Exon 2 of 10	5
MAP2K2	ENST00000599345.1 link	n.597T>C		non_coding_transcript_exon_variant	Exon 3 of 7	5
MAP2K2	ENST00000687128.1 link	n.839T>C		non_coding_transcript_exon_variant	Exon 2 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Feb 23, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 18042262, 24803665, 27763634, 33153128, 33258288, 30867592, 18456719, 19156172, 22177953, 22753777, 26399658, 29493581) -

RASopathy

Pathogenic:2

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 134 of the MAP2K2 protein (p.Tyr134His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 18042262, 18456719). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8274). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MAP2K2 function with a positive predictive value of 95%. This variant disrupts the p.Tyr134 amino acid residue in MAP2K2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18039235, 18413255, 23885229). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.400T>C variant in the MAP2K2 gene is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 134 (p.Tyr134His). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.917, 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). Furthermore, a different pathogenic variant at this residue (Tyr134Cys) has been identified in several patients with RASopathies (PM5). This variant has been identified in at least 6 patients with a RASopathy, of which 2 were unconfirmed de novo cases (PS4, PM6_Strong; Partners LMM, Labcorp internal data, ClinVar: SCV000063166.5, SCV002210187.3; PMID: 18042262, 18456719, 27763634). Western blot assay in Ba/F3 cells showed that the variant activated ERK signaling while the wildtype did not (PS3_Supporting, PMID: 30867592). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4, PM6_Strong, PM1, PM5, PS3_Supprting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) -

Cardiofaciocutaneous syndrome 4

Pathogenic:2

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MAP2K2-related disorder

Pathogenic:1

Jun 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MAP2K2 c.400T>C variant is predicted to result in the amino acid substitution p.Tyr134His. This variant has been reported in individuals with cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome, or a RASopathy (Nyström et al. 2008. PubMed ID: 18456719; Schulz et al. 2008. PubMed ID: 18042262; Terao et al. 2010. PubMed ID: 20518782; Table S1, Bhoj et al. 2017. PubMed ID: 27763634). This variant was reported in at least one of those patients in the de novo state (Nyström et al. 2008. PubMed ID: 18456719). This variant was also reported de novo in an individual with neurodevelopmental disorder, seizure, other neurological anomaly, syndromic/malformative, immune/hematological diseases, cardiovascular disease (Supplemental Data, Case ID 452, Quaio et al. 2020. PubMed ID: 33258288) and in an individual with Erdheim-Chester disease (ECD) (Diamond et al. 2019. PubMed ID: 30867592). Functional studies also showed that this variant alters protein function (Diamond et al. 2019. PubMed ID: 30867592). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is reported as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/8274/). This variant is interpreted as pathogenic. -

Noonan syndrome 1

Pathogenic:1

Molecular Genetics, Centre for Human Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardio-facio-cutaneous syndrome

Pathogenic:1

Nov 24, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Jun 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

1.5

L;.

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-4.4

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.97

Gain of catalytic residue at G135 (P = 0.1401);.;

MVP

0.98

MPC

1.5

ClinPred

1.0

GERP RS

5.3

Varity_R

0.94

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over