chr19-18785050-T-A

Variant names:

• chr19-18785050-T-A
• NM_000095.3:c.1760A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000095.3(COMP):​c.1760A>T​(p.His587Leu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H587R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Likely_pathogenic. Variant got 8 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 chr19-18785050-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMP	NM_000095.3	c.1760A>T	p.His587Leu	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.1760A>T	p.His587Leu	missense_variant	Exon 16 of 19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.1661A>T	p.His554Leu	missense_variant	Exon 15 of 18	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.1601A>T	p.His534Leu	missense_variant	Exon 15 of 18	2		ENSP00000403792.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with COMP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 587 of the COMP protein (p.His587Leu). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.His587 amino acid residue in COMP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9880218, 12768438, 17570134, 20936634; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	.;D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.3	.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.8	D;D;D
REVEL	Pathogenic	0.87
Sift	Benign	0.063	T;D;T
Sift4G	Benign	0.061	T;T;T
Polyphen		1.0	.;D;.
Vest4		0.90
MutPred		0.74		.;Gain of sheet (P = 0.039);.;
MVP		0.93
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.93
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18895860;