ClinVar Genomic variation as it relates to human health
NM_145331.3(MAP3K7):c.1535C>T (p.Pro512Leu)
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.
Pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_145331.3(MAP3K7):c.1535C>T (p.Pro512Leu)
Variation ID: 264698 Accession: VCV000264698.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6q15 6: 90518552 (GRCh38) [ NCBI UCSC ] 6: 91228271 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 3, 2016 Feb 14, 2024 Sep 10, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_145331.3:c.1535C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_663304.1:p.Pro512Leu missense NM_003188.4:c.1454C>T NP_003179.1:p.Pro485Leu missense NM_145332.3:c.1524+706C>T intron variant NM_145333.3:c.1443+706C>T intron variant NC_000006.12:g.90518552G>A NC_000006.11:g.91228271G>A NG_011966.2:g.73637C>T O43318:p.Pro512Leu - Protein change
- P485L, P512L
- Other names
- -
- Canonical SPDI
- NC_000006.12:90518551:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
MAP3K7 | - | - |
GRCh38 GRCh37 |
257 | 282 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Oct 2, 2021 | RCV000254565.5 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 10, 2022 | RCV001530168.10 |
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
Help
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
Help
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Mar 09, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Frontometaphyseal dysplasia 2
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429547.2
First in ClinVar: Aug 16, 2020 Last updated: Jul 27, 2021 |
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Frontometaphyseal dysplasia 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002012036.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence (ClinVar ID: VCV000264698.10, PS1). The variant … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence (ClinVar ID: VCV000264698.10, PS1). The variant has been observed in at least four similarly affected unrelated individuals and reported as de novoo (PMID: 27426733, PS2 and PS4) It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Missense changes are a common disease-causing mechanism (PP2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.802, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Abnormal facial shape (present) , Delayed gross motor development (present) , Tetralogy of Fallot (present) , Cryptorchidism (present) , Epicanthus … (more)
Global developmental delay (present) , Abnormal facial shape (present) , Delayed gross motor development (present) , Tetralogy of Fallot (present) , Cryptorchidism (present) , Epicanthus (present) , Hypertelorism (present) , Microcephaly (present) , Micrognathia (present) , Round face (present) , Congenital hypertrophic pyloric stenosis (present) , Hearing impairment (present) (less)
|
|
Pathogenic
(Oct 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001804564.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28498505, 27620904, 27426733, 25899317, 29660408, 29467388) (less)
|
|
Pathogenic
(Sep 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003440003.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact … (more)
Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 264698). This variant is also known as p.Pro485Leu. This missense change has been observed in individual(s) with frontometaphyseal dysplasia (PMID: 27426733). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 512 of the MAP3K7 protein (p.Pro512Leu). Experimental studies have shown that this missense change affects MAP3K7 function (PMID: 27426733). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Sep 30, 2016)
|
no assertion criteria provided
Method: literature only
|
FRONTOMETAPHYSEAL DYSPLASIA 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000320731.1
First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016 |
Comment on evidence:
In 15 unrelated patients from diverse ethnic backgrounds with frontometaphyseal dysplasia-2 (FMD2; 617137), including 5 patients previously reported by Basart et al. (2015), Wade et … (more)
In 15 unrelated patients from diverse ethnic backgrounds with frontometaphyseal dysplasia-2 (FMD2; 617137), including 5 patients previously reported by Basart et al. (2015), Wade et al. (2016) identified heterozygosity for a c.1454C-T transition (c.1454C-T, NM_003188.3) in the MAP3K7 gene, resulting in a pro485-to-leu (P485L) substitution at a phylogenetically conserved residue immediately N-terminal to the coiled-coil domain, within a region of TAK1 that mediates interactions with TAB2 (605101). In addition to the typical features of FMD, 8 of the 15 patients exhibited keloid scarring. Wade et al. (2016) noted that this recurrent mutation occurs at a hypermutable CpG dinucleotide, where the observation of a C-T transition is expected to be more common than other mutations. Functional analysis in HEK293FT cells demonstrated significantly more autophosphorylation at T187 with the P485L mutant than with wildtype TAK1. In addition, luciferase reporter assay measuring activation of several MAPK targets, including ERK (see 176872), p38 (MAPK14; 600289), and JNK (see MAPK8, 601158), showed significantly enhanced activation with the P485L mutant compared to wildtype TAK1; Western blot analysis confirmed a substantial increase in phosphorylation of p38 with the mutant compared to wildtype. In contrast, luciferase reporter assay of the NFKB (see 164011) pathway showed significantly reduced reporter activity with P485L TAK1 compared to wildtype. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808914.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744913.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
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 |
---|---|---|---|---|
Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia. | Wade EM | American journal of human genetics | 2016 | PMID: 27426733 |
Frontometaphyseal dysplasia and keloid formation without FLNA mutations. | Basart H | American journal of medical genetics. Part A | 2015 | PMID: 25899317 |
Text-mined citations for rs886039230 ...
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.