15-66436777-G-T

Variant names:

• chr15-66436777-G-T
• rs727504819
• NM_002755.4:c.323G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PP2 PM6 PM2 PS2

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: Likely pathogenic reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 9.81
• Publications: 13 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 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002755.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	NM_002755.4	MANE Select	c.323G>T	p.Arg108Leu	missense	Exon 3 of 11	NP_002746.1
	MAP2K1	NM_001411065.1		c.257G>T	p.Arg86Leu	missense	Exon 3 of 10	NP_001397994.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.323G>T	p.Arg108Leu	missense	Exon 3 of 11	ENSP00000302486.5
	MAP2K1	ENST00000685172.1		c.323G>T	p.Arg108Leu	missense	Exon 3 of 10	ENSP00000509604.1
	MAP2K1	ENST00000689951.1		c.323G>T	p.Arg108Leu	missense	Exon 3 of 12	ENSP00000509308.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Cardiofaciocutaneous syndrome 3 Pathogenic:2

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PM2, PM6, PP2, PP3

Jun 28, 2019

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RASopathy Pathogenic:1 Uncertain:1

Aug 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 108 of the MAP2K1 protein (p.Arg108Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MAP2K1-related conditions (PMID: 33057194, 35524774, 35982159). ClinVar contains an entry for this variant (Variation ID: 280446). 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 not expected to disrupt MAP2K1 protein function with a negative predictive value of 80%. 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.

Jul 08, 2025

ClinGen RASopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.323G>T variant in MAP2K1 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 108 (p.Arg108Leu, NM_002755.4). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.831, which is above the RASopathy VCEP threshold of 0.7, evidence that correlates with impact to MAP2K1 function (PP3). MAP2K1, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in 3 probands with features of RASopathy (PS4_supporting; 2.5 pts.; PMID: 35524774, Fulgent Genetics & Baylor College of Medicine internal data (SCV000894927 & SCV005871135, respectively)). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with features of RASopathy (PS2; 3.0 pts.; Fulgent Genetics & Baylor College of Medicine internal data (SCV000894927 & SCV005871135, respectively)). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy, based on the ACMG/AMP Criteria applied, as specified by the ClinGen RASopathy VCEP: PM2_supporting, PP3, PP2, PS4_supporting, PS2; Specifications Version 2.3.0). This variant was originally evaluated by the VCEP as pathogenic on 06/25/2020. It was re-evaluated on 07/08/2025 and downgraded to likely pathogenic, despite one new case of genetic evidence (PMID: 35524774). The change in classification was due to changes in guidelines (downgrading PM2 to PM2_supporting and combining PS2 & PM6).

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Mar 23, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.8
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
Mutation Taster		=7/93	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: rs727504819; hg19: chr15-66729115;