rs312262900

Variant names:

• chr19-18785056-G-A
• rs312262900
• NM_000095.3:c.1754C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-18785056-G-A
• chr19-18785056-G-C
• chr19-18785056-G-T

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.1754C>T​(p.Thr585Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. T585R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 9.82

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 domain TSP C-terminal (size 214) in uniprot entity COMP_HUMAN there are 15 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 chr19-18785056-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 19-18785056-G-A is Pathogenic according to our data. Variant chr19-18785056-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 40995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18785056-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMP	NM_000095.3	c.1754C>T	p.Thr585Met	missense_variant	Exon 16 of 19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.1754C>T	p.Thr585Met	missense_variant	Exon 16 of 19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.1655C>T	p.Thr552Met	missense_variant	Exon 15 of 18	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.1595C>T	p.Thr532Met	missense_variant	Exon 15 of 18	2		ENSP00000403792.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Apr 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies demonstrate that T585M mouse models exhibit slow growth, mildly shortened limbs, degeneration of articular cartilage, and reduced chondrocyte proliferation with cellular disorganization (PMID: 17588960); 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, 23956175, 17570134, 24558358, 21922596, 9463320, 17588960) -

Jan 08, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 585 of the COMP protein (p.Thr585Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with COMP-related skeletal dysplasia (PMID: 9463320, 11565064). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40995). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COMP protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on COMP function (PMID: 17570134, 23956175). For these reasons, this variant has been classified as Pathogenic. -

COMP-related disorder Pathogenic:1

Aug 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COMP c.1754C>T variant is predicted to result in the amino acid substitution p.Thr585Met. This variant has been reported in a few individuals with pseudoachondroplasia (PSACH) or multiple epiphyseal dysplasia (MED) (Briggs et al 1998. PubMed ID: 9463320; Czarny-Ratajczak et al. 2001. PubMed ID: 11565064). Different substitutions affecting the same amino acid residue (p.Thr585Arg and p.Thr585Lys) have also reported in individuals with PSACH and MED (Briggs et al 1998. PubMed ID: 9463320; Briggs. 2014. PubMed ID: 24595329). Functional studies suggest that p.Thr585Met substitution led to a delayed cellular trafficking of COMP protein (Chen et al 2008. PubMed ID: 17570134) and the p.Thr585Met mice are reported to have a phenotype that resembles human pseudoachondroplasia (Piróg-Garcia et al. 2007. PubMed ID: 17588960). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Multiple epiphyseal dysplasia Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	.;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	.;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.95
MutPred		0.91		.;Loss of glycosylation at T585 (P = 0.0302);.;
MVP		0.95
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.88
gMVP		0.77

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: rs312262900; hg19: chr19-18895866;