15-66436818-A-G

Position:

• chr15-66436818-A-G

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PS2 PM2 PP2 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.364A>G (p.Asn122Asp) variant in MAP2K1 was absent from gnomAD (PM2). It has been observed in 3 probands with clinical features of a RASopathy, including 1 de novo occurrence with maternity and paternity confirmed and 2 assumed de novo occurrences (PM2_VS; SCV000271240.2; Otto-von-Guericke-Universität Magdeburg internal communication; Invitae internal data, SCV000947966.1). Of these patients, 2 received a clinical diagnosis of either Noonan syndrome or cardiofaciocutaneous syndrome (PS4_Supporting). Of note, this variant was observed in 1 proband without clinical information who inherited it from a parent with unknown clinical status (GeneDx internal data). The c.364A>G (p.Asm122Asp) variant is located in MAP2K1, 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, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on RASopathy-specific ACMG/AMP criteria (PMID:29493581): PS2_VS, PS4_Supporting, PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576999/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 9.19

Genes affected

MAP2K1 (HGNC:6840): (mitogen-activated protein kinase kinase 1) The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K1	NM_002755.4	c.364A>G	p.Asn122Asp	missense_variant	3/11	ENST00000307102.10
MAP2K1	NM_001411065.1	c.298A>G	p.Asn100Asp	missense_variant	3/10
MAP2K1	XM_011521783.4	c.298A>G	p.Asn100Asp	missense_variant	3/11
MAP2K1	XM_017022411.3	c.364A>G	p.Asn122Asp	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K1	ENST00000307102.10	c.364A>G	p.Asn122Asp	missense_variant	3/11	1	NM_002755.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Mar 16, 2020	The c.364A>G (p.Asn122Asp) variant in MAP2K1 was absent from gnomAD (PM2). It has been observed in 3 probands with clinical features of a RASopathy, including 1 de novo occurrence with maternity and paternity confirmed and 2 assumed de novo occurrences (PM2_VS; SCV000271240.2; Otto-von-Guericke-Universität Magdeburg internal communication; Invitae internal data, SCV000947966.1). Of these patients, 2 received a clinical diagnosis of either Noonan syndrome or cardiofaciocutaneous syndrome (PS4_Supporting). Of note, this variant was observed in 1 proband without clinical information who inherited it from a parent with unknown clinical status (GeneDx internal data). The c.364A>G (p.Asm122Asp) variant is located in MAP2K1, 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, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on RASopathy-specific ACMG/AMP criteria (PMID:29493581): PS2_VS, PS4_Supporting, PM2, PP2. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 27, 2021	- -

Cardiofaciocutaneous syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MNM Diagnostics

Feb 10, 2020

According to ACMG Guidelines, the variant meets the following criteria of pathogenicity: PS2, PS4, PM2, PP2, PP3, PP4. This is a de novo variant of a missense heterozygotic mutation in exon 3 of MAP2K1 gene in position c.364A>G. The change results in the asparagine to aspartate substitution in codon 122. MAP2K1 mutations are responsible for the Cardio-facio-cutaneous Syndrome type 3 (CFCS) observed as well in the proband. -

Cardiofaciocutaneous syndrome 3;C4551602:Noonan syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Noonan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 28, 2015

The p.Asn122Asp variant in MAP2K1 has been identified by our laboratory as a de novo occurrence in 1 individual with clinical features of Noonan syndrome. It wa s absent from large population studies. Computational prediction tools and conse rvation analysis suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Asn122Asp variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.15	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.60
Sift	Benign	0.077	T
Sift4G	Benign	0.16	T
Polyphen		0.89	P
Vest4		0.78
MutPred		0.41		Gain of phosphorylation at Y125 (P = 0.1461);
MVP		0.81
MPC		2.6
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.83
gMVP		0.71

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: rs876657651; hg19: chr15-66729156; COSMIC: COSV61073416;