rs730880511

Positions:

• chr19-4101032-C-A
• chr19-4101032-C-G
• chr19-4101032-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP2 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.692G>T (p.Arg231Leu) variant has been identified in at least 2 independent occurrences in patients with clinical features of RASopathies (PS4_Supporting GeneDx, Invitae internal data, GTR Lab IDs 26957, 500031; ClinVar SCV000207960.9, SCV000551455.2). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.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). Computational prediction tools and conservation analysis suggest that the p.Arg231Leu variant may impact the protein (PP3).In summary, the clinical significance of the p.Arg231Leu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA296133/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 31)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PS4: 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.692G>T	p.Arg231Leu	missense_variant	6/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.692G>T	p.Arg231Leu	missense_variant	6/9		XP_006722862.1
MAP2K2	XM_047439100.1	c.122G>T	p.Arg41Leu	missense_variant	4/9		XP_047295056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.692G>T	p.Arg231Leu	missense_variant	6/11	1	NM_030662.4	ENSP00000262948	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Cardiofaciocutaneous syndrome 4 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Feb 14, 2019

- -

Noonan syndrome with multiple lentigines Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2021

Not observed at significant frequency in large population cohorts (Lek 2016); Missense variants in this gene are often considered pathogenic (Stenson 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with cystic kidney disease (Connaughton 2019); This variant is associated with the following publications: (PMID: 30773290) -

RASopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 02, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAP2K2 protein function. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 231 of the MAP2K2 protein (p.Arg231Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MAP2K2-related conditions (PMID: 30773290). ClinVar contains an entry for this variant (Variation ID: 40818). -

Noonan syndrome and Noonan-related syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

May 10, 2019

The c.692G>T (p.Arg231Leu) variant has been identified in at least 2 independent occurrences in patients with clinical features of RASopathies (PS4_Supporting GeneDx, Invitae internal data, GTR Lab IDs 26957, 500031; ClinVar SCV000207960.9, SCV000551455.2). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.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). Computational prediction tools and conservation analysis suggest that the p.Arg231Leu variant may impact the protein (PP3).In summary, the clinical significance of the p.Arg231Leu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PP2, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	0.39	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.62		Gain of stability (P = 0.0068);.;
MVP		0.93
MPC		1.4
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.84
gMVP		0.79

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: rs730880511; hg19: chr19-4101030;