rs149551600

Positions:

• chr19-18783128-C-G
• chr19-18783128-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000095.3(COMP):​c.2153G>C​(p.Arg718Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R718W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 4.78

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a strand (size 12) in uniprot entity COMP_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000095.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-18783129-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 19-18783128-C-G is Pathogenic according to our data. Variant chr19-18783128-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 65557.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-18783128-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3	c.2153G>C	p.Arg718Pro	missense_variant	18/19	ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7	c.2153G>C	p.Arg718Pro	missense_variant	18/19	1	NM_000095.3	P1
COMP	ENST00000542601.6	c.2054G>C	p.Arg685Pro	missense_variant	17/18	1
COMP	ENST00000425807.1	c.1994G>C	p.Arg665Pro	missense_variant	17/18	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2022

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 718 of the COMP protein (p.Arg718Pro). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the P.Arg718 amino acid residue in COMP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12483304, 14684695, 21834907, 21965141, 24595329). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt COMP protein function. ClinVar contains an entry for this variant (Variation ID: 65557). This missense change has been observed in individuals with COMP-related conditions (PMID: 15756302; Invitae). -

Multiple epiphyseal dysplasia Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.4	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.056	T;D;D
Polyphen		1.0	.;D;.
Vest4		0.97
MutPred		0.89		.;Loss of methylation at R718 (P = 0.0184);.;
MVP		0.93
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.94
gMVP		0.85

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

LitVar

Other links and lift over

dbSNP: rs149551600; hg19: chr19-18893938;