chr19-18786051-C-G

Position:

• chr19-18786051-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000095.3(COMP):​c.1403G>C​(p.Cys468Ser) 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. 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. C468Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.76

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 12 ACMG points.

• PM1: In a disulfide_bond (size 20) in uniprot entity COMP_HUMAN there are 11 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 chr19-18786051-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 19-18786051-C-G is Pathogenic according to our data. Variant chr19-18786051-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 989361.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMP	NM_000095.3	c.1403G>C	p.Cys468Ser	missense_variant	13/19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.1403G>C	p.Cys468Ser	missense_variant	13/19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.1304G>C	p.Cys435Ser	missense_variant	12/18	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.1244G>C	p.Cys415Ser	missense_variant	12/18	2		ENSP00000403792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple epiphyseal dysplasia type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 26, 2019

The COMP c.1403G>C (p.Cys468Ser) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not reported in the Genome Aggregation Database in a region of good sequencing coverage, so the variant is presumed to be rare. Functional studies of the p.Cys468Ser variant have not been conducted, but it affects the seventh type 3 calcium-binding repeat. These repeats play an important role in protein function and are a common site of pathogenic variants, particularly missense variants (Briggs et al. 2002; Tan et al. 2009; Jackson et al. 2012). Cys468 also participates in a disulfide bond. Multiple in silico tools consistently predict a deleterious effect of the p.Cys468Ser variant, and another amino acid change at the same position has been reported as causative for pseudoachondroplasia (Hecht et al. 1995; Xie et al. 2013). Based on the collective evidence, the p.Cys468Ser variant is classified as likely pathogenic for multiple epiphyseal dysplasia. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.5	.;H;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.8	D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.98	.;D;.
Vest4		0.91
MutPred		0.76		.;Gain of phosphorylation at C468 (P = 0.0033);.;
MVP		0.97
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.99
gMVP		0.95

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: rs137852651; hg19: chr19-18896861;