chr15-66481793-G-C

Variant names:

• chr15-66481793-G-C
• rs1057519733
• NM_002755.4:c.607G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_002755.4(MAP2K1):​c.607G>C​(p.Glu203Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E203G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K1 NM_002755.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.88
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-66481794-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 167260.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 15-66481793-G-C is Pathogenic according to our data. Variant chr15-66481793-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1328146.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.607G>C	p.Glu203Gln	missense_variant	Exon 6 of 11	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1	c.463G>C	p.Glu155Gln	missense_variant	Exon 5 of 10		NP_001397994.1
MAP2K1	XM_011521783.4	c.541G>C	p.Glu181Gln	missense_variant	Exon 6 of 11		XP_011520085.1
MAP2K1	XM_017022411.3	c.529G>C	p.Glu177Gln	missense_variant	Exon 5 of 10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.607G>C	p.Glu203Gln	missense_variant	Exon 6 of 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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiofaciocutaneous syndrome 3 Pathogenic:1

Sep 16, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MAP2K1 c.607G>C (p.Glu203Gln) variant is a missense variant which has been reported in a heterozygous state in an eight year old female with cardiofaciocutaneous syndrome, with the variant presumed to have occurred de novo (Nystrom et al. 2008). The proband's phenotype included short stature, intellectual impairment, delayed motor development and brain atrophy. The proband also presented with pulmonic stenosis, an unspecified congenital heart malformation, strabismus and dysmorphic features including ptosis, downslanting palpebral fissures, abnormal low set ears, bitemporal narrowing, broad neck, sparse, dry hair, dry skin and missing eyebrows. The p.Glu203Gln variant is not found in the Genome Aggregation Database version 2.1.1 or version 3.1.1 in a region of good sequence coverage, which suggests the variant is rare. Experimental evidence suggests this variant may have a structural effect on the protein (Cheng et al. 2012). In addition, in a zebrafish embryo model, while expression was not noted to be different between the variant MEK1 and wild-type, statistical analyses evaluating the oval shape of the embryos suggested increased severity in the presence of the p.Glu203Gln variant compared to wild-type (Jindal et al. 2017). The adjacent c.608A>G (p.Glu203Gly) variant has been established as pathogenic for cardiofaciocutaneous syndrome by the RASopathy ClinGen Variant Curation Expert Panel (Gelb et al. 2018). In addition, another substitution at this location, c.608A>C (p.Glu203Ala), has been reported in an individual with cardiofaciocutaneous syndrome (Bertola et al. 2020). Based on the collective evidence, the c.607G>C (p.Glu203Gln) variant is classified as pathogenic for cardiofaciocutaneous syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.90	L;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.58
Sift	Benign	0.22	T;T
Sift4G	Benign	0.33	T;T
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.80		Gain of MoRF binding (P = 0.0599);.;
MVP		0.94
MPC		2.5
ClinPred		0.89	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.63
gMVP		0.81
Mutation Taster		=7/93	disease causing

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: rs1057519733; hg19: chr15-66774131;