VCV000183687.15 - ClinVar

NM_002427.4(MMP13):c.619T>G (p.Trp207Gly)

Germline

Classification

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.

(8)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002427.4(MMP13):c.619T>G (p.Trp207Gly)

Variation ID: 183687 Accession: VCV000183687.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.2 11: 102954174 (GRCh38) [ NCBI UCSC ] 11: 102824903 (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	Apr 21, 2017	May 1, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002427.4:c.619T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002418.1:p.Trp207Gly	missense
NC_000011.10:g.102954174A>C
NC_000011.9:g.102824903A>C
NG_021404.1:g.6561T>G
	P45452:p.Trp207Gly

... more HGVS ... less HGVS

Protein change

W207G

Other names

Canonical SPDI

NC_000011.10:102954173:A:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00020 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

Links

ClinGen: CA186146 UniProtKB: P45452#VAR_073418 OMIM: 600108.0005 dbSNP: rs140059558 VarSome

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
Gene	OMIM	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.
MMP13		-	-	GRCh38 GRCh37	227	319

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.
Metaphyseal chondrodysplasia, Spahr type	Pathogenic (3)	criteria provided, single submitter	Jun 10, 2020	RCV000162347.5
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 3, 2024	RCV000303456.16
Metaphyseal anadysplasia 1, autosomal dominant	Pathogenic (1)	criteria provided, single submitter	Mar 14, 2024	RCV004019951.2

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.
Pathogenic (Jun 10, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metaphyseal chondrodysplasia, Spahr type Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001524343.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Likely pathogenic (Mar 23, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001872883.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24648384, 27576021, … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24648384, 27576021, 31130284, 13915518) (less)
Pathogenic (Jan 03, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001586089.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 24648384‚ 27576021 Comment: This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 207 of the MMP13 protein … (more) This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 207 of the MMP13 protein (p.Trp207Gly). This variant is present in population databases (rs140059558, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive metaphyseal dysplasia, Spahr type (PMID: 24648384, 27576021; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183687). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MMP13 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metaphyseal anadysplasia 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005016605.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024
Likely pathogenic (Aug 02, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000341124.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 24648384‚ 27576021 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MMP13 Number of individuals with the variant: 7 Sex: mixed
Likely pathogenic (Nov 11, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023492.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (May 01, 2014)	no assertion criteria provided Method: literature only	METAPHYSEAL DYSPLASIA, SPAHR TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000212650.2 First in ClinVar: Mar 24, 2015 Last updated: Apr 21, 2017	Publications: PubMed (2) PubMed: 13915518‚ 24648384 Comment on evidence: In 2 affected members of the Swiss family with Spahr type metaphyseal dysplasia (MDST; 250400), originally described by Spahr and Spahr-Hartmann (1961), Bonafe et al. … (more) In 2 affected members of the Swiss family with Spahr type metaphyseal dysplasia (MDST; 250400), originally described by Spahr and Spahr-Hartmann (1961), Bonafe et al. (2014) identified homozygosity for a c.619T-G transversion in the MMP13 gene, resulting in a trp207-to-gly (W207G) substitution at a highly conserved residue in the core of the catalytic domain. The mutation, which was present in heterozygosity in all obligate carriers in the family, was not found in 100 local controls; however, it was detected in 2 of approximately 13,000 unselected alleles in the Exome Variant Server database, for an allelic frequency of approximately 0.00015, which the authors stated was in the range of a very rare recessive allele. (less)
Pathogenic (Jun 06, 2018)	no assertion criteria provided Method: clinical testing	Metaphyseal chondrodysplasia, Spahr type Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV000854742.1 First in ClinVar: Apr 21, 2017 Last updated: Apr 21, 2017

Comment:

This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 207 of the MMP13 protein (p.Trp207Gly). This variant is present in population databases (rs140059558, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive metaphyseal dysplasia, Spahr type (PMID: 24648384, 27576021; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183687). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MMP13 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Metaphyseal dysplasia, Spahr type; missense MMP13 mutations in two Iraqi siblings.	Tadros S	Clinical dysmorphology	2017	PMID: 27576021
MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.	Bonafé L	American journal of medical genetics. Part A	2014	PMID: 24648384
[Familial metaphysial dysostosis. Study of 4 cases in siblings].	SPAHR A	Helvetica paediatrica acta	1961	PMID: 13915518
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MMP13	-	-	-	-

Text-mined citations for rs140059558 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002427.4(MMP13):c.619T>G (p.Trp207Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140059558 ...