19-18785772-G-T

Position:

• chr19-18785772-G-T

Variant summary

Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000095.3(COMP):​c.1569C>A​(p.Asn523Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N523S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.335

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 24 ACMG points.

• PS1: Transcript NM_000095.3 (COMP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 9189
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000095.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 19-18785772-G-T is Pathogenic according to our data. Variant chr19-18785772-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3	c.1569C>A	p.Asn523Lys	missense_variant	14/19	ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7	c.1569C>A	p.Asn523Lys	missense_variant	14/19	1	NM_000095.3	P1
COMP	ENST00000542601.6	c.1470C>A	p.Asn490Lys	missense_variant	13/18	1
COMP	ENST00000425807.1	c.1410C>A	p.Asn470Lys	missense_variant	13/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 12, 2022	For these reasons, this variant has been classified as Pathogenic. 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: 432270). This missense change has been observed in individual(s) with multiple epiphyseal dysplasia (PMID: 9021009, 17133256, 21922596). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 523 of the COMP protein (p.Asn523Lys). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2017	The c.1569 C>A nucleotide substitution, resulting in the N523K amino acid change, has not been reported previously as a pathogenic or benign variant to our knowledge. However, a different nucleotide substitution (c.1569 C>G) that also results in the N523K missense substitution has been previously reported in association with multiple epiphyseal dysplasia (Ballo et al., 1997; Jackson et al., 2012). The N523K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N523K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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 (D518N, D518Y, D518H, D518G, T527A, T529A, T529I) 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. We interpret N523K as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.70
MutPred		0.89		.;Gain of solvent accessibility (P = 0.012);.;
MVP		0.76
ClinPred		1.0	D
GERP RS		-3.4
Varity_R		0.90
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137852654; hg19: chr19-18896582;