NM_002755.4(MAP2K1):c.388T>C (p.Tyr130His) AND Cardio-facio-cutaneous syndrome

Germline classification:: Likely pathogenic (2 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:: RCV000037596.15

Allele description [Variation Report for NM_002755.4(MAP2K1):c.388T>C (p.Tyr130His)]

NM_002755.4(MAP2K1):c.388T>C (p.Tyr130His)

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.388T>C (p.Tyr130His)

Other names:

NM_002755.3(MAP2K1):c.388T>C

HGVS:

NC_000015.10:g.66436842T>C
NG_008305.1:g.54970T>C
NM_002755.4:c.388T>CMANE SELECT
NP_002746.1:p.Tyr130His
NP_002746.1:p.Tyr130His
LRG_725t1:c.388T>C
LRG_725:g.54970T>C
LRG_725p1:p.Tyr130His
NC_000015.9:g.66729180T>C
NM_002755.3:c.388T>C
c.388T>C

Protein change:

Y130H

Links:

dbSNP: rs397516793

NCBI 1000 Genomes Browser:

rs397516793

Molecular consequence:

NM_002755.4:c.388T>C - 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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Rhodoblastus sphagnicola strain DSM 16996 scaffold0083, whole genome shotgun seq...
Rhodoblastus sphagnicola strain DSM 16996 scaffold0083, whole genome shotgun sequence
gi|1347325706|gb|NHSJ01000083.1||gn :NHSJ01|scaffold0083

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061255	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 7, 2012)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19156172, 17366577, 16439621, 17551924, 18042262, 24033266
SCV000616533	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Likely pathogenic (May 9, 2017)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 19156172, 29493581 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061255

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Mar 7, 2012)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000616533

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Likely pathogenic
(May 9, 2017)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome.

Narumi Y, Aoki Y, Niihori T, Neri G, Cavé H, Verloes A, Nava C, Kavamura MI, Okamoto N, Kurosawa K, Hennekam RC, Wilson LC, Gillessen-Kaesbach G, Wieczorek D, Lapunzina P, Ohashi H, Makita Y, Kondo I, Tsuchiya S, Ito E, Sameshima K, Kato K, et al.

Am J Med Genet A. 2007 Apr 15;143A(8):799-807.

PubMed [citation]

PMID:: 17366577

Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.

Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, McCormick F, Rauen KA.

Science. 2006 Mar 3;311(5765):1287-90. Epub 2006 Jan 26.

PubMed [citation]

PMID:: 16439621

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061255.5

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

Description

The Tyr130His variant has been reported in one individual with clinical features of Cardio-facio-cutaneous syndrome and was shown to have occurred de novo (Dent ici 2009). In addition, Tyr130Cys and Tyr130Asn have been reported in several i ndividuals with CFC and tyrosine at position 130 represents the most commonly mu tated amino acid in MEK1 (Gripp 2007, Rodriguez-Viciana 2006, Dentici 2009, Naru mi 2007, Schulz 2008). In summary, this variant meets our criteria to be classi fied as pathogenic (http://pcpgm.partners.org/LMM). The presence of a heterozygo us pathogenic variant in MEK1 is consistent with a diagnosis of cardio-facio-cut aneous syndrome but this information should be reconciled with the complete clin ical history of this individual.

#	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		1	not provided	1	not provided

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616533.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

The c.388T>C (p.Tyr130His) variant in MAP2K1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19156172). 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). A different pathogenic missense variant has been previously identified at this codon of MAP2K1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 13351). 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 likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM5, PM2, PM1, PP3, PP2.

#	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 3, 2024

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