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

Clinical significance:Likely pathogenic (Last evaluated: May 9, 2017)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:

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

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

MAP2K1:mitogen-activated protein kinase kinase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_002755.4(MAP2K1):c.388T>C (p.Tyr130His)
Other names:
  • NC_000015.10:g.66436842T>C
  • NG_008305.1:g.54970T>C
  • NM_002755.3:c.388T>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
  • c.388T>C
Protein change:
dbSNP: rs397516793
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_002755.3:c.388T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002755.4:c.388T>C - missense variant - [Sequence Ontology: SO:0001583]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000061255Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
(Mar 7, 2012)
germlineclinical testing

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

SCV000616533ClinGen RASopathy Variant Curation Expert Panelreviewed by expert panel
Likely pathogenic
(May 9, 2017)

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration



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]

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]
See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000061255.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)


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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616533.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)


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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

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