19-18787500-C-G

Position:

• chr19-18787500-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000095.3(COMP):​c.1126G>C​(p.Asp376His) 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. D376G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.02

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 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr19-18787499-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2861303.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 19-18787500-C-G is Pathogenic according to our data. Variant chr19-18787500-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1415145.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3	c.1126G>C	p.Asp376His	missense_variant	10/19	ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7	c.1126G>C	p.Asp376His	missense_variant	10/19	1	NM_000095.3	P1
COMP	ENST00000542601.6	c.1027G>C	p.Asp343His	missense_variant	9/18	1
COMP	ENST00000425807.1	c.967G>C	p.Asp323His	missense_variant	9/18	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp376 amino acid residue in COMP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15756302; Invitae). 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 expected to disrupt COMP protein function. This missense change has been observed in individuals with clinical features of COMP-related conditions (PMID: 21965141; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 376 of the COMP protein (p.Asp376His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.76	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.22	.;B;.
Vest4		0.93
MutPred		0.66		.;Gain of catalytic residue at D376 (P = 0.0565);.;
MVP		0.91
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.99
gMVP		0.98

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: chr19-18898309;