ClinVar Genomic variation as it relates to human health
NM_002755.4(MAP2K1):c.169A>C (p.Lys57Gln)
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.169A>C (p.Lys57Gln)
Variation ID: 40779 Accession: VCV000040779.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.31 15: 66435115 (GRCh38) [ NCBI UCSC ] 15: 66727453 (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 Feb 24, 2015 Feb 14, 2024 May 9, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002755.4:c.169A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002746.1:p.Lys57Gln missense NC_000015.10:g.66435115A>C NC_000015.9:g.66727453A>C NG_008305.1:g.53243A>C LRG_725:g.53243A>C LRG_725t1:c.169A>C LRG_725p1:p.Lys57Gln - Protein change
- K57Q
- Other names
- p.K57Q:AAG>CAG
- NM_002755.3(MAP2K1):c.169A>C
- Canonical SPDI
- NC_000015.10:66435114:A: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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Likely pathogenic (1) |
criteria provided, single submitter
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Feb 11, 2016 | RCV000037591.8 | |
Likely pathogenic (3) |
reviewed by expert panel
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May 9, 2017 | RCV000158014.11 |
Submissions - Germline
Classification
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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
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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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Likely pathogenic
(May 09, 2017)
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reviewed by expert panel
Method: curation
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Noonan syndrome and Noonan-related syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen RASopathy Variant Curation Expert Panel
Accession: SCV000616537.4
First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.169A>C (p.Lys57Gln) 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.169A>C (p.Lys57Gln) 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; Partners LMM GeneDx internal data 26957, 21766; ClinVar SCV000061249.5; SCV000207949.2). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Lys57Gln variant may impact the protein (PP3). 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). 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, PM2, PP3, PP2. (less)
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Likely pathogenic
(Feb 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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Cardio-facio-cutaneous syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061249.5
First in ClinVar: May 03, 2013 Last updated: Dec 19, 2017 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
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Uncertain significance
(Jun 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001568953.4
First in ClinVar: Apr 13, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces lysine with glutamine at codon 57 of the MAP2K1 protein (p.Lys57Gln). The lysine residue is highly conserved and there is a … (more)
This sequence change replaces lysine with glutamine at codon 57 of the MAP2K1 protein (p.Lys57Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant has not been reported in the literature in individuals with MAP2K1-related disease. ClinVar contains an entry for this variant (Variation ID: 40779). Experimental studies have shown that this missense change causes increased downstream phosphorylation of ERK (PMID: 18632602). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency). (less)
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Likely pathogenic
(Feb 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Rasopathy
Rasopathy
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000207949.3
First in ClinVar: Feb 24, 2015 Last updated: Sep 01, 2019 |
Comment:
To our knowledge, this variant has neither been published as a Pathogenic variant, nor has it been reported as a benign polymorphism. The K57Q missense … (more)
To our knowledge, this variant has neither been published as a Pathogenic variant, nor has it been reported as a benign polymorphism. The K57Q missense change is considered to be a non-conservative amino acid substitution, as a positively charged residue (Lys) is replaced by a neutral residue (Gln) at a position in the protein that is highly conserved across species and within related proteins. Furthermore, missense changes in nearby codons (F53S and T55P) have previously been reported in association with cardio-facio-cutaneous syndrome and Costello syndrome, respectively, which are other disorders of the RAS/MAPK pathway (Rodriguez - Viciana et al., 2006; Nava et al., 2007). Therefore, K57Q is considered to be a likely pathogenic variant. (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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MEK1 and AKT2 mutations in Japanese lung cancer. | Sasaki H | Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer | 2010 | PMID: 20354455 |
Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. | Marks JL | Cancer research | 2008 | PMID: 18632602 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5fa3b275-1dad-4c57-bed5-dd904a8b11bb | - | - | - | - |
Text-mined citations for rs397516790 ...
HelpRecord last updated Feb 14, 2024
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.