15-66436824-C-T

Position:

• chr15-66436824-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS3 PS2 PM2 PP3 PP2 PM1

This summary comes from the ClinGen Evidence Repository: The c.370C>T (p.Pro124Ser) variant in MAP2K1 has been observed as a de novo occurrence with maternity and paternity confirmed in 2 probands with features of a RASopathy (PS2_VeryStrong; GeneDx internal data, ClinVar SCV000572401.5). In vitro functional studies provide some evidence that the p.Pro124Ser variant may impact protein function (PS3; PMID:22197931). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). The p.Pro124Ser variant is located in the MAP2K1 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 MAP2K1 (PM1; PMID:29493581). Computational prediction tools and conservation analysis suggest that the p.Leu92Arg 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): PS2_VeryStrong, PS3, PM1, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602456/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 7.79

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]

MAP2K1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: 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
MAP2K1	NM_002755.4	c.370C>T	p.Pro124Ser	missense_variant	3/11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.304C>T	p.Pro102Ser	missense_variant	3/10		NP_001397994.1
MAP2K1	XM_011521783.4	c.304C>T	p.Pro102Ser	missense_variant	3/11		XP_011520085.1
MAP2K1	XM_017022411.3	c.370C>T	p.Pro124Ser	missense_variant	3/10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.370C>T	p.Pro124Ser	missense_variant	3/11	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 15, 2023	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. This variant disrupts the p.Pro124 amino acid residue in MAP2K1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17366577, 27862862, 28049852; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MAP2K1 function (PMID: 22197931, 26343583). 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 not expected to disrupt MAP2K1 protein function. ClinVar contains an entry for this variant (Variation ID: 375981). This missense change has been observed in individual(s) with clinical features of cardio-facio-cutaneous syndrome (PMID: 32978145; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 124 of the MAP2K1 protein (p.Pro124Ser). -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Jul 02, 2020	The c.370C>T (p.Pro124Ser) variant in MAP2K1 has been observed as a de novo occurrence with maternity and paternity confirmed in 2 probands with features of a RASopathy (PS2_VeryStrong; GeneDx internal data, ClinVar SCV000572401.5). In vitro functional studies provide some evidence that the p.Pro124Ser variant may impact protein function (PS3; PMID: 22197931). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). The p.Pro124Ser variant is located in the MAP2K1 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 MAP2K1 (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Leu92Arg 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): PS2_VeryStrong, PS3, PM1, PM2, PP2, PP3. -

Cardiofaciocutaneous syndrome 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

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not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2020

Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with a neurodevelopmental disorder to our knowledge; This variant is associated with the following publications: (PMID: 22197931, 32978145) -

Noonan syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.076	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.83		Loss of stability (P = 0.0746);
MVP		0.82
MPC		2.4
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.67
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057519732; hg19: chr15-66729162; COSMIC: COSV61068297;