rs121434499

Positions:

• chr19-4110559-A-G
• chr19-4110559-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS4_Moderate PM2 PP2 PP3 PM1

This summary comes from the ClinGen Evidence Repository: The c.400T>C (p.Tyr134His) variant in MAP2K2 was absent from large population studies (PM2). It has been identified in 3 patients with Cardiofaciocutaneous syndrome and 1 with Noonan syndrome (PS4_Moderate; SCV000063166.5, Hopital Universitaire Robert Debre internal data, PMIDs: 18042262, 27763634)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). Moreover, a different pathogenic missense variant (p.Tyr134Cys) has been previously identified at this codon of MAP2K2 which may indicate that this residue is critical to the function of the protein (PM5 not met; ClinVar 177868). 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). Computational prediction tools and conservation analysis suggest that the p.Tyr134His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Moderate, PM1, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA119417/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 9.10

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• 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.
• PP2: 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/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.400T>C	p.Tyr134His	missense_variant	3/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.400T>C	p.Tyr134His	missense_variant	3/9		XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.400T>C	p.Tyr134His	missense_variant	3/11	1	NM_030662.4	ENSP00000262948.4
MAP2K2	ENST00000394867.9	n.839T>C		non_coding_transcript_exon_variant	2/10	5
MAP2K2	ENST00000599345.1	n.597T>C		non_coding_transcript_exon_variant	3/7	5
MAP2K2	ENST00000687128.1	n.839T>C		non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2023	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) -

Cardiofaciocutaneous syndrome 4 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -

RASopathy Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The c.400T>C (p.Tyr134His) variant in MAP2K2 has been identified in patients with clinical features of a RASopathy (PS4_Supporting; PMID 18042262; GeneDx, Partners LMM, University of Magdeburg internal data; GTR Lab ID: 26957, 21766, 506381 ClinVar SCV000063166.5). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). A different pathogenic missense variant (p.Tyr134Cys) has been previously identified at this codon of MAP2K2 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 177868). 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.Tyr134His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PM5, PP2, PM1, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 14, 2023	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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt MAP2K2 function. ClinVar contains an entry for this variant (Variation ID: 8274). 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. This variant is not present in population databases (gnomAD no frequency). 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). For these reasons, this variant has been classified as Pathogenic. -

MAP2K2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2023

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

Likely pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics, Centre for Human Genetics

-

- -

Cardio-facio-cutaneous syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2008

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.93	D
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	D
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

Other links and lift over

dbSNP: rs121434499; hg19: chr19-4110557;