chr15-66435221-T-G

Variant names:

• chr15-66435221-T-G
• rs397516791
• NM_002755.4:c.275T>G

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4_Moderate PM6 PP3 PP2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.275T>G variant in the MAP2K1 gene is a missense variant predicted to cause substitution of leucine by arginine at amino acid 92 (p.Leu92Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.793 (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). This variant has been reported in 4 independent patients with clinical feature of a RASopathy, 1 as a confirmed de novo occurrence and 2 as unconfirmed de novo occurrences (PS4_Moderate, PM6_VeryStrong; GeneDx, APHP-Robert Debré hospital, Laboratory for Molecular Medicine internal data; ClinVar SCV000207940.11, SCV000965969.1, SCV000061251.5, PMID:35524774). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PM6_VeryStrong, PS4_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134601/MONDO:0015280/045

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 7.90
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• cardiofaciocutaneous syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 7 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.
• 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 rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.275T>G	p.Leu92Arg	missense_variant	Exon 2 of 11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.209T>G	p.Leu70Arg	missense_variant	Exon 2 of 10		NP_001397994.1
MAP2K1	XM_011521783.4	c.209T>G	p.Leu70Arg	missense_variant	Exon 2 of 11		XP_011520085.1
MAP2K1	XM_017022411.3	c.275T>G	p.Leu92Arg	missense_variant	Exon 2 of 10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.275T>G	p.Leu92Arg	missense_variant	Exon 2 of 11	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Cardio-facio-cutaneous syndrome Pathogenic:2

Feb 11, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 13, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A novel L92R variant that is likely pathogenic was identified in the MAP2K1 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It has, however, been observed to be inherited in an apparently de novo manner in two patients tested at GeneDx. 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. L92R 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 that is conserved across species; however, in in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

RASopathy Pathogenic:1

Sep 17, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.275T>G variant in the MAP2K1 gene is a missense variant predicted to cause substitution of leucine by arginine at amino acid 92 (p.Leu92Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.793 (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). This variant has been reported in 4 independent patients with clinical feature of a RASopathy, 1 as a confirmed de novo occurrence and 2 as unconfirmed de novo occurrences (PS4_Moderate, PM6_VeryStrong; GeneDx, APHP-Robert Debré hospital, Laboratory for Molecular Medicine internal data; ClinVar SCV000207940.11, SCV000965969.1, SCV000061251.5, PMID: 35524774). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PM6_VeryStrong, PS4_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024) -

Noonan syndrome and Noonan-related syndrome Uncertain:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	-0.29	N
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.047	D
Polyphen		0.73	P
Vest4		0.80
MutPred		0.40		Gain of MoRF binding (P = 0.0045);
MVP		0.99
MPC		2.7
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.85
gMVP		0.84
Mutation Taster		=30/70	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516791; hg19: chr15-66727559;