19-18785050-T-C

Position:

• chr19-18785050-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000095.3(COMP):​c.1760A>G​(p.His587Arg) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 4.80

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 16 ACMG points.

• PM1: In a region_of_interest Mediates cell survival and induction of the IAP family of survival proteins (size 230) in uniprot entity COMP_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000095.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 19-18785050-T-C is Pathogenic according to our data. Variant chr19-18785050-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18785050-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMP	NM_000095.3	c.1760A>G	p.His587Arg	missense_variant	16/19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.1760A>G	p.His587Arg	missense_variant	16/19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.1661A>G	p.His554Arg	missense_variant	15/18	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.1601A>G	p.His534Arg	missense_variant	15/18	2		ENSP00000403792.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 13, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects COMP function (PMID: 17570134, 20936634). 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 COMP protein function. ClinVar contains an entry for this variant (Variation ID: 40996). This missense change has been observed in individuals with pseudoachondroplasia (PMID: 9880218, 12768438; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 587 of the COMP protein (p.His587Arg). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2016	The H587R missense variant in the COMP gene has been reported previously in association with Pseudoachondroplasia (PSACH) (Deere et al., 1998). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although H587R is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (T585K/R/M, E583K) have been reported in the Human Gene Mutation Database in association with COMP-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional studies have shown that, although the H587R variant yields minimal effects on collagen binding and secondary protein structure, it disrupts fibril formation and organization (Spitznagel et a., 2004; Schmitz et al., 2006; Weirich et al., 2007; Hansen et al., 2011). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.3	.;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Pathogenic	0.89
Sift	Benign	0.030	D;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.89
MutPred		0.87		.;Gain of sheet (P = 0.0827);.;
MVP		0.90
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.92
gMVP		0.82

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: rs312262901; hg19: chr19-18895860;