19-18787500-C-T

Variant names:

• chr19-18787500-C-T
• rs1555791556
• NM_000095.3:c.1126G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000095.3(COMP):​c.1126G>A​(p.Asp376Asn) 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 (★). 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: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.02
• Publications: 1 publications found

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]

COMP Gene-Disease associations (from GenCC):

• multiple epiphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pseudoachondroplasia

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina
• multiple epiphyseal dysplasia type 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 VariationId is 2861303.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 127 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.78 (below the threshold of 3.09). Trascript score misZ: 1.5018 (below the threshold of 3.09). GenCC associations: The gene is linked to pseudoachondroplasia, multiple epiphyseal dysplasia type 1, multiple epiphyseal dysplasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 19-18787500-C-T is Pathogenic according to our data. Variant chr19-18787500-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1676245.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMP	NM_000095.3	c.1126G>A	p.Asp376Asn	missense_variant	Exon 10 of 19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.1126G>A	p.Asp376Asn	missense_variant	Exon 10 of 19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.1027G>A	p.Asp343Asn	missense_variant	Exon 9 of 18	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.967G>A	p.Asp323Asn	missense_variant	Exon 9 of 18	2		ENSP00000403792.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple epiphyseal dysplasia type 1 Pathogenic:1

Apr 05, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in COMP is predicted to replace aspartic acid with asparagine at codon 376, p.(Asp376Asn). The aspartic acid residue is highly conserved (100 vertebrates, UCSC), and is located in the type-3 consensus motif in thrombospondin type-3 repeat 4, that is characteristic of a calcium-binding pocket and a critical functional domain (PMID: 24595329). There is a small physicochemical difference between aspartic acid and asparagine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in at least three probands a clinical diagnosis of multiple epiphyseal dysplasia (PMID: 17133256, 24595329; Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (4/5 algorithms). Other missense variants (c.1127A>T, p.Asp376Val; c.1126G>C, p.Asp376His; c.1126G>T p.Asp376Tyr) in the same codon with larger physicochemical differences have been reported in patients with multiple epiphyseal dysplasia or pseudoachondroplasia (PMID: 15756302, 21965141, 33030144). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_Moderate, PM1, PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	.;D;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.8	.;H;.
PhyloP100		6.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.082	.;B;.
Vest4		0.72
MutPred		0.81		.;Loss of sheet (P = 0.1907);.;
MVP		0.87
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.97
gMVP		0.98
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs1555791556; hg19: chr19-18898309;