NM_002755.4(MAP2K1):c.389A>G (p.Tyr130Cys) AND Cardio-facio-cutaneous syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: May 9, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000208757.16

Allele description [Variation Report for NM_002755.4(MAP2K1):c.389A>G (p.Tyr130Cys)]

NM_002755.4(MAP2K1):c.389A>G (p.Tyr130Cys)

Gene:

MAP2K1:mitogen-activated protein kinase kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q22.31

Genomic location:

Preferred name:

NM_002755.4(MAP2K1):c.389A>G (p.Tyr130Cys)

Other names:

p.Y130C:TAT>TGT; NM_002755.3(MAP2K1):c.389A>G

HGVS:

NC_000015.10:g.66436843A>G
NG_008305.1:g.54971A>G
NM_002755.4:c.389A>GMANE SELECT
NP_002746.1:p.Tyr130Cys
NP_002746.1:p.Tyr130Cys
LRG_725t1:c.389A>G
LRG_725:g.54971A>G
LRG_725p1:p.Tyr130Cys
NC_000015.9:g.66729181A>G
NM_002755.3:c.389A>G
Q02750:p.Tyr130Cys
c.389A>G

Protein change:

Y130C; TYR130CYS

Links:

UniProtKB: Q02750#VAR_035094; OMIM: 176872.0002; dbSNP: rs121908595

NCBI 1000 Genomes Browser:

rs121908595

Molecular consequence:

NM_002755.4:c.389A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cardio-facio-cutaneous syndrome
Synonyms:: Cardiofaciocutaneous syndrome; CFC syndrome
Identifiers:: MONDO: MONDO:0015280; MedGen: C1275081; Orphanet: 1340; OMIM: PS115150

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061256	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Aug 30, 2016)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17551924, 16439621, 19156172, 18042262, 17366577, 17567882, 17981815, 24033266
SCV000264638	GeneReviews	no classification provided	not provided	germline	literature only
SCV000616532	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (May 9, 2017)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 18413255, 17981815, 18042262, 23093928, 17551924, 16439621 Citation Link,
SCV000698036	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 26, 2016)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 18042262, 22848035, 17551924, 24637312, 16439621, 17981815, 17366577, 24236184, 18632602, 19156172, 23093928, 17567882 LabCorp Variant Classification Summary - May 2015.docx Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	5	5	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome.

Rodriguez-Viciana P, Rauen KA.

Methods Enzymol. 2008;438:277-89. doi: 10.1016/S0076-6879(07)38019-1.

PubMed [citation]

PMID:: 18413255

See all PubMed Citations (14)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061256.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (8)

Description

The p.Tyr130Cys variant in MAP2K1 has been reported in >15 individuals with clin ical features of Cardio-facio-cutaneous (CFC) syndrome and occurred de novo in a t least 10 individuals (Rodriguez-Viciana 2006, Gripp 2007, Narumi 2007, Schulz 2008, Dentici 2009, LMM data). This variant was absent from large population stu dies. In vitro functional studies provide some evidence that this variant may im pact protein function (Rodriguez-Viciana 2006). Computational prediction tools a nd conservation analysis suggest that the p.Tyr130Cys variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. In summary, this variant meets criteria to be classified as pathogenic for CF C in an autosomal dominant manner based on multiple de novo occurrences and abse nce from controls.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		5	not provided	5	not provided

From GeneReviews, SCV000264638.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616532.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

The c.389A>G (p.Tyr130Cys) variant in MAP2K1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStong; PMID 16439621, 17551924, 18042262). In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815). 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). 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 pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PP3, PS3, PM2, PP2, PM1.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698036.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

Variant summary: The c.389A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant. This variant is not found in approximately 121830 control chromosomes. The variant has been reported in several CFC patients including multiple confirmed de novo occurrences, a very strong evidence for pathogenic outcome. A functional study by Rodriguez-Viciana et al 2006 also showed the variant to have an activating effect on ERK phosphorylation, consistent with disease mechanism in CFC. Several clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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