ClinVar Genomic variation as it relates to human health
NM_002755.4(MAP2K1):c.158T>C (p.Phe53Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002755.4(MAP2K1):c.158T>C (p.Phe53Ser)
Variation ID: 13350 Accession: VCV000013350.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.31 15: 66435104 (GRCh38) [ NCBI UCSC ] 15: 66727442 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 23, 2013 Dec 11, 2022 May 9, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002755.4:c.158T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002746.1:p.Phe53Ser missense NC_000015.10:g.66435104T>C NC_000015.9:g.66727442T>C NG_008305.1:g.53232T>C LRG_725:g.53232T>C LRG_725t1:c.158T>C LRG_725p1:p.Phe53Ser Q02750:p.Phe53Ser - Protein change
- F53S
- Other names
- p.F53S:TTT>TCT
- NM_002755.3(MAP2K1):c.158T>C
- Canonical SPDI
- NC_000015.10:66435103:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MAP2K1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
497 | 585 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Feb 1, 2008 | RCV000014278.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 2, 2016 | RCV000158002.2 | |
Pathogenic (2) |
reviewed by expert panel
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May 9, 2017 | RCV000520164.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 09, 2017)
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reviewed by expert panel
Method: curation
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Cardio-facio-cutaneous syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen RASopathy Variant Curation Expert Panel
Accession: SCV000616530.4
First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.158T>C (p.Phe53Ser) variant in MAP2K1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of … (more)
The c.158T>C (p.Phe53Ser) 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 16439621). In vitro functional studies provide some evidence that the p.Phe53Ser variant may impact protein function (PS3; PMID 16439621). 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.Phe53Ser 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): PM6, PS3, PM2, PP2, PM1, PP3. (less)
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Pathogenic
(Jun 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000207937.11
First in ClinVar: Feb 24, 2015 Last updated: Oct 09, 2016 |
Comment:
The F53S variant in the MAP2K1 gene has been published previously as de novo in a patient with cardio-facio-cutaneous syndrome (Rodriguez-Viciana et al., 2006). The … (more)
The F53S variant in the MAP2K1 gene has been published previously as de novo in a patient with cardio-facio-cutaneous syndrome (Rodriguez-Viciana et al., 2006). 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. F53S 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 that is conserved across species. Functional studies have shown that F53S results in increased phosphorylation of ERK (Rodriguez-Viciana et al., 2008). Additionally, the F53 residue is analagous to the F57 residue in MEK2, which is a known hotspot for variants (Rodriguez-Viciana et al., 2008). Therefore, we consider this variant to be pathogenic. (less)
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Pathogenic
(Jan 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardio-facio-cutaneous syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074175.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Comment:
Variant summary: MAP2K1 c.158T>C (p.Phe53Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: MAP2K1 c.158T>C (p.Phe53Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251374 control chromosomes. c.158T>C has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (example, Rodrigues-Viciana_2006, Yoon_2007, Siegel_2011, Bessis_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significant stimulation of ERK phosphorylation relative to the wild-type control (example, Rodriguez-Viciana_2008). One clinical diagnostic laboratory and an expert panel (ClinGen RASopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 01, 2008)
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no assertion criteria provided
Method: literature only
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CARDIOFACIOCUTANEOUS SYNDROME 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034527.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 24, 2020 |
Comment on evidence:
In a patient with cardiofaciocutaneous syndrome (CFC3; 615279), Rodriguez-Viciana et al. (2006) identified a T-to-C transition at nucleotide 158 (c.158T-C, NM_002755) of the MEK1 gene … (more)
In a patient with cardiofaciocutaneous syndrome (CFC3; 615279), Rodriguez-Viciana et al. (2006) identified a T-to-C transition at nucleotide 158 (c.158T-C, NM_002755) of the MEK1 gene resulting in a phenylalanine-to-serine substitution at codon 53 (F53S). This mutation was not identified in either of the patient's parents. Interestingly, a mutation at the equivalent codon in MEK2 (601263) was found in another CFC patient (F57C; 601263.0001). By in vitro studies, Senawong et al. (2008) found that MEK1 mutants F53S and Y130C and the MEK2 mutant F57C could not induce ERK signaling unless phosphorylated by RAF at 2 homologous serine residues in the regulatory loop. When these serine residues were replaced with alanines, ERK phosphorylation was significantly reduced in the presence of RAF. However, the F57C MEK2 mutant was less dependent on RAF signaling than the other mutants. This difference resulted in F57C MEK2 being resistant to the selective RAF inhibitor SB-590885. However, all 3 mutants were sensitive to the MEK inhibitor U0126. Senawong et al. (2008) suggested that MEK inhibition could have potential therapeutic value in CFC. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Cardio-facio-cutaneous syndrome-associated pathogenic MAP2K1 variants activate autophagy. | Chen J | Gene | 2020 | PMID: 31972311 |
Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients. | Bessis D | The British journal of dermatology | 2019 | PMID: 30141192 |
A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines. | Nishi E | American journal of medical genetics. Part A | 2015 | PMID: 25423878 |
Dermatological findings in 61 mutation-positive individuals with cardiofaciocutaneous syndrome. | Siegel DH | The British journal of dermatology | 2011 | PMID: 21062266 |
Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. | Rodriguez-Viciana P | Methods in enzymology | 2008 | PMID: 18413255 |
Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options. | Senawong T | Human molecular genetics | 2008 | PMID: 17981815 |
Neurological complications of cardio-facio-cutaneous syndrome. | Yoon G | Developmental medicine and child neurology | 2007 | PMID: 18039235 |
Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. | Rodriguez-Viciana P | Science (New York, N.Y.) | 2006 | PMID: 16439621 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b78d797f-9630-4e8f-a1e3-8bf3ece401f5 | - | - | - | - |
Text-mined citations for rs121908594 ...
HelpRecord last updated Dec 11, 2022
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.