rs397516790

Positions:

• chr15-66435115-A-C
• chr15-66435115-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PP2 PP3 PS4_Moderate PS2 PM2 PM6 PM1

This summary comes from the ClinGen Evidence Repository: The c.169A>C (p.Lys57Gln) variant in MAP2K1 was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been reported in 3 total patients with clinical features of a RASopathy (PS4_Moderate; SCV000061249.5; Otto von Guericke University Magdeburg internal data; Invitae internal data). One was a confirmed de novo occurrence and one was an unconfirmed de novo occurrence (PS2; PM6; SCV000061249.5; Otto von Guericke University Magdeburg internal data). The p.Lys57Gln variant is located in the negative regulatory region, which 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.Lys57Gln variant may impact the protein (PP3). Furthermore, the 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 variants are common (PP2; PMID:29493581). 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, PS4_Moderate, PM2, PM6, PM1, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA134595/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• 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 14 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K1	NM_002755.4	c.169A>C	p.Lys57Gln	missense_variant	2/11	ENST00000307102.10
MAP2K1	NM_001411065.1	c.103A>C	p.Lys35Gln	missense_variant	2/10
MAP2K1	XM_011521783.4	c.103A>C	p.Lys35Gln	missense_variant	2/11
MAP2K1	XM_017022411.3	c.169A>C	p.Lys57Gln	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K1	ENST00000307102.10	c.169A>C	p.Lys57Gln	missense_variant	2/11	1	NM_002755.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2019	To our knowledge, this variant has neither been published as a Pathogenic variant, nor has it been reported as a benign polymorphism. The K57Q missense change is considered to be a non-conservative amino acid substitution, as a positively charged residue (Lys) is replaced by a neutral residue (Gln) at a position in the protein that is highly conserved across species and within related proteins. Furthermore, missense changes in nearby codons (F53S and T55P) have previously been reported in association with cardio-facio-cutaneous syndrome and Costello syndrome, respectively, which are other disorders of the RAS/MAPK pathway (Rodriguez - Viciana et al., 2006; Nava et al., 2007). Therefore, K57Q is considered to be a likely pathogenic variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 24, 2018	This sequence change replaces lysine with glutamine at codon 57 of the MAP2K1 protein (p.Lys57Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant has not been reported in the literature in individuals with MAP2K1-related disease. ClinVar contains an entry for this variant (Variation ID: 40779). Experimental studies have shown that this missense change causes increased downstream phosphorylation of ERK (PMID: 18632602). 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 is not present in population databases (ExAC no frequency). -
Likely pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The c.169A>C (p.Lys57Gln) variant in MAP2K1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; Partners LMM GeneDx internal data 26957, 21766; ClinVar SCV000061249.5; SCV000207949.2). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Lys57Gln variant may impact the protein (PP3). The 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). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM2, PP3, PP2. -

Cardio-facio-cutaneous syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2016

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.066	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.33		Loss of ubiquitination at K57 (P = 0.0027);
MVP		0.96
MPC		2.6
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.90

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: rs397516790; hg19: chr15-66727453;