NM_145331.3(MAP3K7):c.502G>C (p.Gly168Arg) AND Frontometaphyseal dysplasia 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 3, 2016
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:: RCV000254566.3

Allele description [Variation Report for NM_145331.3(MAP3K7):c.502G>C (p.Gly168Arg)]

NM_145331.3(MAP3K7):c.502G>C (p.Gly168Arg)

Gene:

MAP3K7:mitogen-activated protein kinase kinase kinase 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q15

Genomic location:

Preferred name:

NM_145331.3(MAP3K7):c.502G>C (p.Gly168Arg)

HGVS:

NC_000006.12:g.90556605C>G
NG_011966.2:g.35584G>C
NM_003188.4:c.502G>C
NM_145331.3:c.502G>CMANE SELECT
NM_145332.3:c.502G>C
NM_145333.3:c.502G>C
NP_003179.1:p.Gly168Arg
NP_663304.1:p.Gly168Arg
NP_663305.1:p.Gly168Arg
NP_663306.1:p.Gly168Arg
NC_000006.11:g.91266324C>G
NM_003188.3:c.502G>C
O43318:p.Gly168Arg

Protein change:

G168R; GLY168ARG

Links:

UniProtKB: O43318#VAR_077345; OMIM: 602614.0004; dbSNP: rs886039233

NCBI 1000 Genomes Browser:

rs886039233

Molecular consequence:

NM_003188.4:c.502G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_145331.3:c.502G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_145332.3:c.502G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_145333.3:c.502G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Frontometaphyseal dysplasia 2 (FMD2)
Identifiers:: MONDO: MONDO:0014935; MedGen: C4310697; OMIM: 617137

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000320734	OMIM	no assertion criteria provided	Pathogenic (Oct 3, 2016)	germline	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

SCV000320734

OMIM

no assertion criteria provided

Pathogenic
(Oct 3, 2016)

germline

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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.

Wade EM, Daniel PB, Jenkins ZA, McInerney-Leo A, Leo P, Morgan T, Addor MC, Adès LC, Bertola D, Bohring A, Carter E, Cho TJ, Duba HC, Fletcher E, Kim CA, Krakow D, Morava E, Neuhann T, Superti-Furga A, Veenstra-Knol I, Wieczorek D, Wilson LC, et al.

Am J Hum Genet. 2016 Aug 4;99(2):392-406. doi: 10.1016/j.ajhg.2016.05.024. Epub 2016 Jul 15.

PubMed [citation]

PMID:: 27426733
PMCID:: PMC4974064

Details of each submission

From OMIM, SCV000320734.2

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

Description

In a Brazilian male patient with a mild form of frontometaphyseal dysplasia-2 (FMD2; 617137), Wade et al. (2016) identified heterozygosity for a de novo c.502G-C transversion (c.502G-C, NM_003188.3) in the MAP3K7 gene, resulting in a gly168-to-arg (G168R) substitution at a highly conserved residue within the kinase domain of TAK1. The proband did not exhibit some of the features commonly seen in patients with FMD, including small chin, hearing loss, downslanting palpebral fissures, and flared metaphyses. Functional analysis in HEK293FT cells demonstrated significantly more autophosphorylation at T187 with the G168R mutant than with wildtype TAK1. However, luciferase reporter assay measuring activation of MAPK targets, as well as immunoblot for phosphorylation of p38 (MAPK14; 600289), showed no increase in signaling with the G168R mutant compared to wildtype TAK1. In addition, luciferase reporter assay of the NFKB (see 164011) pathway showed significantly reduced reporter activity with G168R TAK1 compared to wildtype.

#	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		not provided	not provided	not provided	not provided

Last Updated: Apr 23, 2022

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