rs193922900

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP3

The NM_000095.3(COMP):c.1417_1419delGAC(p.Asp473del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

COMP
NM_000095.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.87

Publications

2 publications found

Variant links:

Genes affected

COMP (HGNC:2227): (cartilage oligomeric matrix protein) The protein encoded by this gene is a noncollagenous extracellular matrix (ECM) protein. It consists of five identical glycoprotein subunits, each with EGF-like and calcium-binding (thrombospondin-like) domains. Oligomerization results from formation of a five-stranded coiled coil and disulfides. Binding to other ECM proteins such as collagen appears to depend on divalent cations. Contraction or expansion of a 5 aa aspartate repeat and other mutations can cause pseudochondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). [provided by RefSeq, Jul 2016]

COMP Gene-Disease associations (from GenCC):

multiple epiphyseal dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pseudoachondroplasia
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina
multiple epiphyseal dysplasia type 1
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

COMP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000095.3

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-18786034-TGTC-T is Pathogenic according to our data. Variant chr19-18786034-TGTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 40988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP3

Nonframeshift variant in repetitive region in NM_000095.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMP	NM_000095.3 link	c.1417_1419delGAC	p.Asp473del	conservative_inframe_deletion	Exon 13 of 19	ENST00000222271.7	NP_000086.2	P49747-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COMP	ENST00000222271.7 link	c.1417_1419delGAC	p.Asp473del	conservative_inframe_deletion	Exon 13 of 19	1	NM_000095.3	ENSP00000222271.2	P49747-1
COMP	ENST00000542601.6 link	c.1318_1320delGAC	p.Asp440del	conservative_inframe_deletion	Exon 12 of 18	1		ENSP00000439156.2	G3XAP6
COMP	ENST00000425807.1 link	c.1258_1260delGAC	p.Asp420del	conservative_inframe_deletion	Exon 12 of 18	2		ENSP00000403792.1	P49747-2
COMP	ENST00000612179.1 link	n.81_83delGAC		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

250042

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461476

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727048

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60388

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome

Pathogenic:3Other:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The in-frame deletion p.D473del in COMP (NM_000095.3) has been observed in individual(s) with pseudoachondroplasia and spondyloepiphyseal dysplasia ( J T Hecht et al, 1995; Jackson et al, 2011; Huang et al, 2018). This variant has been reported to affect COMP protein function ( Chen et al, 2008; Hartley et al, 2013). Additionally, the variant has been reported to ClinVar as Pathogenic. The p.D473del variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant results in a deletion of a aspartic acid at position 473 of the COMP gene. However, as this is an in-frame deletion, it is not expected to result in either a truncated protein product or loss of protein through nonsense-mediated mRNA decay. The nucleotide c.1417 in COMP is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Sep 25, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM4 moderate, PM6 moderate -

May 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not provided

Pathogenic:3

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1417_1419del, results in the deletion of 1 amino acid(s) of the COMP protein (p.Asp473del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with pseudoachondroplasia and spondyloepiphyseal dysplasia (PMID: 7670471, 21922596, 30138938). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40988). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects COMP function (PMID: 11084047, 17570134, 22006726, 23956175). For these reasons, this variant has been classified as Pathogenic. -

Nov 20, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 11, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Most common pathogenic variant in the COMP gene and has been reported previously in association with pseudoachondroplasia (Hecht et al., 1995; Suleman et al., 2012; Briggs et al., 2014); Published functional studies in mice demonstrate abnormal growth plates with disorganized chondrocyte columns resulting in the development of short-limb dwarfism (Suleman et al., 2012); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32347019, 29309831, 7670471, 24595329, 17570134, 11084047, 22006726, 23956175, 30138938) -

Multiple epiphyseal dysplasia type 1

Pathogenic:2

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed inframe deletion c.1417_1419del(p.Asp473del) variant in COMP gene has been reported in multiple individuals affected with COMP related disease (Jacob P, et. al., 2022; Briggs MD, et. al., 2014). Experimental studies have shown that this variant affects COMP function (Hartley CL, et. al., 2013). The p.Asp473del variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). This p.Asp473del causes deletion of amino acid Aspartic Acid at position 473. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 02, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 7670471, 17570134, 23956175, 22006726, 11084047] -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.9

Mutation Taster

=32/68

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over