VCV000009198.14 - ClinVar

NM_000095.3(COMP):c.2152C>T (p.Arg718Trp)

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_000095.3(COMP):c.2152C>T (p.Arg718Trp)

Variation ID: 9198 Accession: VCV000009198.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.11 19: 18783129 (GRCh38) [ NCBI UCSC ] 19: 18893939 (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 1, 2013	Feb 14, 2024	Nov 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000095.3:c.2152C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000086.2:p.Arg718Trp	missense
NC_000019.10:g.18783129G>A
NC_000019.9:g.18893939G>A
NG_007070.1:g.13176C>T
	P49747:p.Arg718Trp

... more HGVS ... less HGVS

Protein change

R718W

Other names

Canonical SPDI

NC_000019.10:18783128:G:A

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.

0.00100 (T)

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

Links

ClinGen: CA340882 UniProtKB: P49747#VAR_066827 OMIM: 600310.0017 dbSNP: rs28936368 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.
COMP		-	-	GRCh38 GRCh37	671	680

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.
Multiple epiphyseal dysplasia type 1	Likely pathogenic (2)	criteria provided, single submitter	-	RCV000009776.8
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 28, 2023	RCV001268837.12
Multiple epiphyseal dysplasia	not provided (1)	no classification provided	-	RCV002054432.2
Carpal tunnel syndrome 2	Pathogenic (1)	no assertion criteria provided	Dec 1, 2003	RCV001289465.1

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 (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001448039.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Multiple epiphyseal dysplasia (present) Sex: male
Pathogenic (Nov 21, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001832279.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
Likely pathogenic (May 11, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003924689.1 First in ClinVar: May 20, 2023 Last updated: May 20, 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: 24595329, 21965141, 17133256, 21834907, 18328978, 29162415, 15880723, 26691295, 21042783, 14684695, 32686688, 12483304) (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple epiphyseal dysplasia type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004100353.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Comment: The missense variant p.R718W in COMP (NM_000095.3) has been reported previously in affected indviduals with multiple epihyseal dysplasia (Briggs MD et al,Jakkula E et al,Mabuchi … (more) The missense variant p.R718W in COMP (NM_000095.3) has been reported previously in affected indviduals with multiple epihyseal dysplasia (Briggs MD et al,Jakkula E et al,Mabuchi A et al). It has been submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. In silico tools predict the variant to be damaging and the residue is semi conserved across species. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Arthralgia (present) , Decreased circulating vitamin D concentration (present) , Multiple epiphyseal dysplasia (present)
Pathogenic (Nov 28, 2023)	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: SCV001588971.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 12483304‚ 14684695‚ 21834907‚ 21965141‚ 24595329 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 718 of the COMP protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 718 of the COMP protein (p.Arg718Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple epiphyseal dysplasia (PMID: 12483304, 14684695, 21834907, 21965141, 24595329). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9198). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COMP protein function. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 01, 2003)	no assertion criteria provided Method: literature only	EPIPHYSEAL DYSPLASIA, MULTIPLE, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029997.3 First in ClinVar: Apr 04, 2013 Last updated: Jan 26, 2021	Publications: PubMed (3) PubMed: 12483304‚ 14684695‚ 32686688 Comment on evidence: Multiple Epiphyseal Dysplasia 1 In a patient with a severe form of multiple epiphyseal dysplasia-1 (EDM1; 132400), Mabuchi et al. (2003) identified a 2152C-T transition … (more) Multiple Epiphyseal Dysplasia 1 In a patient with a severe form of multiple epiphyseal dysplasia-1 (EDM1; 132400), Mabuchi et al. (2003) identified a 2152C-T transition in exon 18 of the COMP gene, resulting in an arg718-to-trp (R718W) substitution. Jakkula et al. (2003) identified the same mutation in patients with EDM1 who had muscle weakness, moderate creatine kinase elevation, and EDM beginning with the knee joints. No disease-causing mutations were detected in collagen IX genes. Carpal Tunnel Syndrome 2 In affected members of a large 4-generation family (family 2) with carpal tunnel syndrome (CTS2; 619161) as well as signs of EDM, Li et al. (2020) identified heterozygosity for the c.2152C-T transition (c.2152C-T, NM_000095.3) in the COMP gene resulting in the R718W mutation. The mutation segregated fully with disease in the family and was not found in human genome variation databases. Functional analysis showed that secretion of the R718W mutant was reduced in both primary tendon cells and chondrocytes compared to wildtype COMP. (less)
Pathogenic (Dec 01, 2003)	no assertion criteria provided Method: literature only	CARPAL TUNNEL SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001477295.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (3) PubMed: 12483304‚ 14684695‚ 32686688 Comment on evidence: Multiple Epiphyseal Dysplasia 1 In a patient with a severe form of multiple epiphyseal dysplasia-1 (EDM1; 132400), Mabuchi et al. (2003) identified a 2152C-T transition … (more) Multiple Epiphyseal Dysplasia 1 In a patient with a severe form of multiple epiphyseal dysplasia-1 (EDM1; 132400), Mabuchi et al. (2003) identified a 2152C-T transition in exon 18 of the COMP gene, resulting in an arg718-to-trp (R718W) substitution. Jakkula et al. (2003) identified the same mutation in patients with EDM1 who had muscle weakness, moderate creatine kinase elevation, and EDM beginning with the knee joints. No disease-causing mutations were detected in collagen IX genes. Carpal Tunnel Syndrome 2 In affected members of a large 4-generation family (family 2) with carpal tunnel syndrome (CTS2; 619161) as well as signs of EDM, Li et al. (2020) identified heterozygosity for the c.2152C-T transition (c.2152C-T, NM_000095.3) in the COMP gene resulting in the R718W mutation. The mutation segregated fully with disease in the family and was not found in human genome variation databases. Functional analysis showed that secretion of the R718W mutant was reduced in both primary tendon cells and chondrocytes compared to wildtype COMP. (less)
not provided (-)	no classification provided Method: literature only	Multiple epiphyseal dysplasia Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000086693.3 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1123 BookShelf: NBK1123

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; This variant is associated with the following publications: (PMID: 24595329, 21965141, 17133256, 21834907, 18328978, 29162415, 15880723, 26691295, 21042783, 14684695, 32686688, 12483304)

Comment:

The missense variant p.R718W in COMP (NM_000095.3) has been reported previously in affected indviduals with multiple epihyseal dysplasia (Briggs MD et al,Jakkula E et al,Mabuchi A et al). It has been submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. In silico tools predict the variant to be damaging and the residue is semi conserved across species. For these reasons, this variant has been classified as Pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 718 of the COMP protein (p.Arg718Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple epiphyseal dysplasia (PMID: 12483304, 14684695, 21834907, 21965141, 24595329). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9198). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COMP protein function. 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
Multiple Epiphyseal Dysplasia, Autosomal Dominant.	Adam MP	-	2024	PMID: 20301302
Mutations in COMP cause familial carpal tunnel syndrome.	Li C	Nature communications	2020	PMID: 32686688
Genotype to phenotype correlations in cartilage oligomeric matrix protein associated chondrodysplasias.	Briggs MD	European journal of human genetics : EJHG	2014	PMID: 24595329
Revisit of multiple epiphyseal dysplasia: ethnic difference in genotypes and comparison of radiographic features linked to the COMP and MATN3 genes.	Kim OH	American journal of medical genetics. Part A	2011	PMID: 21965141
A mutation in cartilage oligomeric matrix protein (COMP) causes early-onset osteoarthritis in a large kindred study.	Mu SC	Annals of human genetics	2011	PMID: 21834907
A recurrent R718W mutation in COMP results in multiple epiphyseal dysplasia with mild myopathy: clinical and pathogenetic overlap with collagen IX mutations.	Jakkula E	Journal of medical genetics	2003	PMID: 14684695
Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia.	Mabuchi A	Human genetics	2003	PMID: 12483304

Text-mined citations for rs28936368 ...

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_000095.3(COMP):c.2152C>T (p.Arg718Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28936368 ...