15-66436825-C-T

Position:

• chr15-66436825-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_002755.4(MAP2K1):​c.371C>T​(p.Pro124Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• 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 17 ACMG points.

• PM1: In a domain Protein kinase (size 293) in uniprot entity MP2K1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002755.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAP2K1. . Gene score misZ 3.1085 (greater than the threshold 3.09). Trascript score misZ 3.7499 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 3, Costello syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 15-66436825-C-T is Pathogenic according to our data. Variant chr15-66436825-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.371C>T	p.Pro124Leu	missense_variant	3/11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.305C>T	p.Pro102Leu	missense_variant	3/10		NP_001397994.1
MAP2K1	XM_011521783.4	c.305C>T	p.Pro102Leu	missense_variant	3/11		XP_011520085.1
MAP2K1	XM_017022411.3	c.371C>T	p.Pro124Leu	missense_variant	3/10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.371C>T	p.Pro124Leu	missense_variant	3/11	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiofaciocutaneous syndrome 3 Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 09, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect - CFC International	-	Variant interpreted as Pathogenic and reported on 08-24-2020 by lab or GTR ID Mendelics. GenomeConnect - CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 13, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Cardio-facio-cutaneous syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 02, 2010	The Pro124Leu variant has been identified in one individual with clinical featur es of Cardio-facio-cutaneous syndrome (Narumi 2007). In addition, a different am ino acid change at this location (Pro124Gln) was identified as a de novo variant in an indidual with clinical features of Cardio-facio-cutaneous syndrome and Co stello syndrome (Gripp 2007). Therefore, this variant is likely to be pathogenic . -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2017	Variant summary: The MAP2K1 c.371C>T (p.Pro124Leu) variant causes a missense change involving the alteration of a highly conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest is absent from large, broad control datasets of ExAC and gnomAD (~121408 and 246224 control chromosomes tested). This variant was reported as a germline variant in at least one patient with presented with Cardio-Facio-Cutaneous syndrome (CFC) (Narumi_MAP2K2_AJMG_2007). This variant is also reported as a somatic change in multiple types of cancer, including melanoma (Chang_NatBiotech_2016, Trunzer_JofClinOnc_2013). In the zebrafish embryonic assay the variant was causing dysmorphology and increased embryonic lethality. In addition, other alteration of the same codon, c.371C>A (P124Q) have been reported as a de novo change in CFC patient (Gripp, 2007). Lastly, one clinical diagnostic laboratory and a literature review via ClinVar classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2023	Functional studies examining the morphological effect of P124L in zebrafish show a significant effect on oval shape, lethality, and heart size (PMID: 28049852); Published functional studies demonstrate a damaging effect with increased phosphorylation of ERK (PMID: 19915144); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (PMID: 29493581); This variant is associated with the following publications: (PMID: 34522120, 34758253, 17366577, 24803665, 28191890, 28714951, 31785789, 32641410, 25370473, 22753777, 19156172, 26399658, 22177953, 29493581, 36442478, 28049852, 19915144, 27862862) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MAP2K1: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP2, PP3 -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 15, 2018

- -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 124 of the MAP2K1 protein (p.Pro124Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MAP2K1-related conditions (PMID: 17366577, 27862862; Invitae). ClinVar contains an entry for this variant (Variation ID: 40744). 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 MAP2K1 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MAP2K1 function (PMID: 28049852). 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: 17551924, 28049852, 32005694, 32978145). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.92		Loss of catalytic residue at N122 (P = 0.1104);
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.88
gMVP		0.78

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: rs397516792; hg19: chr15-66729163; COSMIC: COSV61068422;