NM_002755.4(MAP2K1):c.167A>C (p.Gln56Pro) AND Melorheostosis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 23, 2020
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV002051704.9

Allele description [Variation Report for NM_002755.4(MAP2K1):c.167A>C (p.Gln56Pro)]

NM_002755.4(MAP2K1):c.167A>C (p.Gln56Pro)

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.167A>C (p.Gln56Pro)

HGVS:

NC_000015.10:g.66435113A>C
NG_008305.1:g.53241A>C
NM_002755.4:c.167A>CMANE SELECT
NP_002746.1:p.Gln56Pro
NP_002746.1:p.Gln56Pro
LRG_725t1:c.167A>C
LRG_725:g.53241A>C
LRG_725p1:p.Gln56Pro
NC_000015.9:g.66727451A>C
NM_002755.3:c.167A>C

Protein change:

Q56P; GLN56PRO

Links:

OMIM: 176872.0006; dbSNP: rs1057519729

NCBI 1000 Genomes Browser:

rs1057519729

Molecular consequence:

NM_002755.4:c.167A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Melorheostosis (MEL)
Synonyms:: MELORHEOSTOSIS, ISOLATED
Identifiers:: MONDO: MONDO:0007970; MedGen: C3149631; Orphanet: 2485; OMIM: 155950; Human Phenotype Ontology: HP:6000817

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001364399	OMIM	no assertion criteria provided	Pathogenic (Jun 23, 2020)	somatic	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001364399

OMIM

no assertion criteria provided

Pathogenic
(Jun 23, 2020)

somatic

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	somatic	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Somatic activating mutations in MAP2K1 cause melorheostosis.

Kang H, Jha S, Deng Z, Fratzl-Zelman N, Cabral WA, Ivovic A, Meylan F, Hanson EP, Lange E, Katz J, Roschger P, Klaushofer K, Cowen EW, Siegel RM, Marini JC, Bhattacharyya T.

Nat Commun. 2018 Apr 11;9(1):1390. doi: 10.1038/s41467-018-03720-z.

PubMed [citation]

PMID:: 29643386
PMCID:: PMC5895796

Details of each submission

From OMIM, SCV001364399.1

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

Description

In samples of affected bone from 3 patients (Melo-4, Melo-9, and Melo-19) with melorheostosis (MEL; 155950), Kang et al. (2018) identified somatic mosaicism for a c.167A-C transversion (c.167A-C, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a gln56-to-pro (Q56P) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency ranged from 9 to 28% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Analysis of overlying skin in patient Melo-4 showed the variant at an allele frequency of 12.5%. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) compared to cells from unaffected bone, confirming a gain-of-function effect with the Q56P variant, and the level of ERK1/2 activation by MEK1 generally correlated with mutant allele frequency.

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

Last Updated: Nov 10, 2024

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