15-66436837-G-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002755.4(MAP2K1):c.383G>T(p.Gly128Val) 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G128D) has been classified 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:5
• Conservation: PhyloP100: 9.86

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 23 ACMG points.

• PS1: Transcript NM_002755.4 (MAP2K1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 40745
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002755.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-66436837-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1297058.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, MAP2K1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 15-66436837-G-T is Pathogenic according to our data. Variant chr15-66436837-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K1	NM_002755.4	c.383G>T	p.Gly128Val	missense_variant	3/11	ENST00000307102.10
MAP2K1	NM_001411065.1	c.317G>T	p.Gly106Val	missense_variant	3/10
MAP2K1	XM_011521783.4	c.317G>T	p.Gly106Val	missense_variant	3/11
MAP2K1	XM_017022411.3	c.383G>T	p.Gly128Val	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K1	ENST00000307102.10	c.383G>T	p.Gly128Val	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/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2023	Transgenic Zebra fish model with the p.(G128V) variant demonstrated features consistent with a RASopathy (Jindal et al., 2017); Identified in a newborn patient with congenital heart disease in published literature (Hakami et al., 2016); 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; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 26918529, 25370473, 22753777, 19156172, 26399658, 22177953, 29493581, 18042262, 31972311, 28049852) -

Cardiofaciocutaneous syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2008

- -

Cardio-facio-cutaneous syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 21, 2014

The p.Gly128Val variant in MAP2K1 has been previously identified in 2 individual s with clinical features of Cardio-facio-cutaneous syndrome (Schulz 2008, LMM un published data) and was identified to occur de novo in one of these individuals (Schulz 2008). It was absent from large population studies. Computational predic tion tools and conservation analysis suggest that the p.Gly128Val variant may im pact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the p.Gly128Val variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MAP2K1 function (PMID: 19376813, 28049852). 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. ClinVar contains an entry for this variant (Variation ID: 13352). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 1804226, 18039235, 18413255, 21062266). 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 glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 128 of the MAP2K1 protein (p.Gly128Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	0.82	L
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Loss of catalytic residue at I126 (P = 0.08);
MVP		0.98
MPC		2.8
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121908596; hg19: chr15-66729175; COSMIC: COSV61068483;