15-66436777-G-T

Position:

• chr15-66436777-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS2 PM6 PM2 PP3 PP2

This summary comes from the ClinGen Evidence Repository: The c.323G>T (p.Arg108Leu) variant in MAP2K1 was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed as a de novo occurrence in 2 probands, one of whom had maternity and paternity confirmed (PS2, PM6; Fulgent Genetics and Baylor Genetics internal data, ClinVar SCV000894927.1). 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). Computational prediction tools and conservation analysis suggest that the p.Arg108Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PM2, PM6, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603467/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 9.81

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 10 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.323G>T	p.Arg108Leu	missense_variant	3/11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.257G>T	p.Arg86Leu	missense_variant	3/10		NP_001397994.1
MAP2K1	XM_011521783.4	c.257G>T	p.Arg86Leu	missense_variant	3/11		XP_011520085.1
MAP2K1	XM_017022411.3	c.323G>T	p.Arg108Leu	missense_variant	3/10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.323G>T	p.Arg108Leu	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:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Cardiofaciocutaneous syndrome 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jun 28, 2019

- -

RASopathy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Jun 25, 2020

The c.323G>T (p.Arg108Leu) variant in MAP2K1 was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed as a de novo occurrence in 2 probands, one of whom had maternity and paternity confirmed (PS2, PM6; Fulgent Genetics and Baylor Genetics internal data, ClinVar SCV000894927.1). 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). Computational prediction tools and conservation analysis suggest that the p.Arg108Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PM2, PM6, PP2, PP3. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2016

The R108L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R108L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the protein kinase domain that is conserved across species; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Cardiofaciocutaneous syndrome 3;C4551602:Noonan syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	0.84	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.051	T
Polyphen		0.61	P
Vest4		0.85
MutPred		0.69		Gain of ubiquitination at K104 (P = 0.0331);
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.91

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: rs727504819; hg19: chr15-66729115;