chr15-66436842-T-C

Position:

• chr15-66436842-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP3 PM6_Strong PS4_Supporting PM5

This summary comes from the ClinGen Evidence Repository: The c.388T>C (p.Tyr130His) variant in MAP2K1 has been reported as an unconfirmed de novo occurrence in two probands with clinical features of a RASopathy (PM6_Strong; PMID:1915617, Ambry Genetics internal data, ClinVar SCV000740998.1). One of these patients had a clinical diagnosis of cardiofaciocutaneous syndrome (PS4_Supporting). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). 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). 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 not applied; PMID 29493581). Moreover, a different pathogenic missense variant has been previously identified at this codon of MAP2K1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 13351). Computational prediction tools and conservation analysis suggest that the p.Tyr130His 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): PS4_Supporting, PM6_Strong, PM5, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA279999/MONDO:0015280/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.90

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 11 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.388T>C	p.Tyr130His	missense_variant	3/11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.322T>C	p.Tyr108His	missense_variant	3/10		NP_001397994.1
MAP2K1	XM_011521783.4	c.322T>C	p.Tyr108His	missense_variant	3/11		XP_011520085.1
MAP2K1	XM_017022411.3	c.388T>C	p.Tyr130His	missense_variant	3/10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.388T>C	p.Tyr130His	missense_variant	3/11	1	NM_002755.4	ENSP00000302486	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Cardio-facio-cutaneous syndrome Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The c.388T>C (p.Tyr130His) 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; PMID 19156172). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). 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). A different pathogenic missense variant has been previously identified at this codon of MAP2K1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 13351). Computational prediction tools and conservation analysis suggest that the p.Tyr130Cys variant may impact the protein (PP3). 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, PM5, PM2, PM1, PP3, PP2. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 07, 2012	The Tyr130His variant has been reported in one individual with clinical features of Cardio-facio-cutaneous syndrome and was shown to have occurred de novo (Dent ici 2009). In addition, Tyr130Cys and Tyr130Asn have been reported in several i ndividuals with CFC and tyrosine at position 130 represents the most commonly mu tated amino acid in MEK1 (Gripp 2007, Rodriguez-Viciana 2006, Dentici 2009, Naru mi 2007, Schulz 2008). In summary, this variant meets our criteria to be classi fied as pathogenic (http://pcpgm.partners.org/LMM). The presence of a heterozygo us pathogenic variant in MEK1 is consistent with a diagnosis of cardio-facio-cut aneous syndrome but this information should be reconciled with the complete clin ical history of this individual. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2015

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 12, 2019

The MAP2K1 c.388T>C; p.Tyr130His variant (rs397516793) is reported in the literature in individuals affected with cardio-facio-cutaneous (CFC) syndrome, including at least one de novo occurence (Dentici 2009). This variant is reported in ClinVar (Variation ID: 40747), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 130is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, tyrosine 130 is considered a mutational hotspot (Bromberg-White 2012), and other variants at this codon (c.389A>G; p.Tyr130Cys, c.388T>A; p.Tyr130Asn) have been reported in individuals with CFC syndrome and are considered pathogenic (Dentici 2009, Gripp 2007, Rodriguez-Viciana 2008). In vitro functional analyses demonstrate that the p.Tyr130His variant leads to overactivation of the MAP2K1 protein (Hao 2008). Based on available information, the p.Tyr130His variant is considered to be pathogenic. References: Bromberg-White JL et al. MEK genomics in development and disease. Brief Funct Genomics. 2012 Jul;11(4):300-10. Dentici ML et al. Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations. Eur J Hum Genet. 2009 Jun;17(6):733-40. Gripp KW et al. Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. Am J Med Genet A. 2007 Jul 1;143A(13):1472-80. Hao YH et al. Structural requirements for Yersinia YopJ inhibition of MAP kinase pathways. PLoS One. 2008 Jan 2;3(1):e1375. Rodriguez-Viciana P and Rauen KA. Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. Methods Enzymol. 2008;438:277-89. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.98		Gain of catalytic residue at G131 (P = 0.1382);
MVP		0.99
MPC		2.8
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.83

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: rs397516793; hg19: chr15-66729180; COSMIC: COSV61073592;