19-18783129-G-A

Position:

• chr19-18783129-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000095.3(COMP):​c.2152C>T​(p.Arg718Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R718P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 0.404

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 18 ACMG points.

• PM1: In a disulfide_bond (size 221) in uniprot entity COMP_HUMAN there are 19 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 chr19-18783128-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 19-18783129-G-A is Pathogenic according to our data. 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. Variant chr19-18783129-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMP	NM_000095.3	c.2152C>T	p.Arg718Trp	missense_variant	18/19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.2152C>T	p.Arg718Trp	missense_variant	18/19	1	NM_000095.3	ENSP00000222271	P1
COMP	ENST00000542601.6	c.2053C>T	p.Arg685Trp	missense_variant	17/18	1		ENSP00000439156
COMP	ENST00000425807.1	c.1993C>T	p.Arg665Trp	missense_variant	17/18	2		ENSP00000403792

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458542 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Multiple epiphyseal dysplasia type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2003	- -

Carpal tunnel syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2003

- -

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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.86
MutPred		0.80		.;Loss of methylation at R718 (P = 0.0184);.;
MVP		0.86
ClinPred		1.0	D
GERP RS		-0.68
Varity_R		0.79
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs28936368; hg19: chr19-18893939;