2-20006173-G-A

Position:

• chr2-20006173-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_002381.5(MATN3):​c.361C>T​(p.Arg121Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R121Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MATN3 NM_002381.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 0.690

Genes affected

MATN3 (HGNC:6909): (matrilin 3) This gene encodes a member of von Willebrand factor A domain containing protein family. This family of proteins is thought to be involved in the formation of filamentous networks in the extracellular matrices of various tissues. This protein contains two von Willebrand factor A domains; it is present in the cartilage extracellular matrix and has a role in the development and homeostasis of cartilage and bone. Mutations in this gene result in multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_002381.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-20006172-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 2-20006173-G-A is Pathogenic according to our data. Variant chr2-20006173-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-20006173-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATN3	NM_002381.5	c.361C>T	p.Arg121Trp	missense_variant	2/8	ENST00000407540.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATN3	ENST00000407540.8	c.361C>T	p.Arg121Trp	missense_variant	2/8	1	NM_002381.5	P1
MATN3	ENST00000421259.2	c.361C>T	p.Arg121Trp	missense_variant	2/7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461648 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple epiphyseal dysplasia type 5 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 31, 2021	This MATN3 variant (rs104893637) is absent from a large population dataset and has an entry in ClinVar. It has been identified in approximately 40 percent of individuals with EDM5. Three bioinformatics tools queried predict that p.Arg121Trp would be damaging. The arginine residue at this position is conserved across most vertebrate species assessed. Analysis of cartilage from a patient with the p.Arg121Trp variant showed retention of matrilin-3 protein within the rough endoplasmic reticulum (rER) of chondrocytes. This variant is not predicted to affect normal exon 2 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.361C>T to be likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 07, 2022	The MATN3 c.361C>T variant is classified as a PATHOGENIC variant (PS4, PM1, PM2, PP3, PP4) This variant is a single nucleotide change in the MATN3 gene which is predicted to change the amino acid arginine at position 121 in the protein to tryptophan. The variant is in exon 2/8 of the MATN3 gene and is located in protein domain: von Willebrand factor A-like domain (vWF A-domain), of the MATN3 gene. Studies have demonstrated that MED mutations in MATN3 are predominantly located in exon 2, which encodes the vWF A-domain (PMID: 16287128; 15459972) (PM1). The variant has been reported in dbSNP (rs104893637) but is absent from population databases (PM2). This variant has been known as a common disease causing variant in the MATN3 gene, and has been reported many times in individuals affected with MED (PMID: 11479597, 21965141, 14729835, 16287128, 15459972, GeneReview) (PS4). The variant has been reported in ClinVar (Variation ID: 7541) as likely pathogenic (1)/ pathogenic (2). The variant has been reported in HGMD (Accession#: CM012401) as disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3). Patient's phenotype is highly specific for a the MATN3 gene (PP4). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 27, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MATN3 function (PMID: 16199550, 18518980). 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 MATN3 protein function. ClinVar contains an entry for this variant (Variation ID: 7541). This missense change has been observed in individual(s) with multiple epiphyseal dysplasia (PMID: 11479597, 14729835). 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 121 of the MATN3 protein (p.Arg121Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -

Spondyloepimetaphyseal dysplasia, matrilin-3 type Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory of Genetic Skeletal Anomaly, Seoul National University Children's Hospital

-

- -

Multiple epiphyseal dysplasia Other:1

not provided, no classification provided

literature only

GeneReviews

-

European-based studies have identified p.Arg121Trp in 12/33 and p.Thr120Met in 5/33 affected individuals (total = 52%) [Chapman et al 2001; Mostert et al 2003; Jackson et al 2004; Cotterill et al 2005; Fresquet et al 2007; Jackson et al 2012; Author, unpublished data]. In a Japanese population, p.Arg121Trp was identified in 3/9 and p.Thr120Met in 3/9 affected individuals (total = 66%) [Mabuchi et al 2004, Itoh et al 2006]. In a Korean study, p.Arg121Trp was identified in 20/30 and p.Thr120Met was identified in 4/30 affected individuals (total = 80%) [Kim et al 2011]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.39	N
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.95		Loss of methylation at R121 (P = 0.0876);Loss of methylation at R121 (P = 0.0876);
MVP		0.99
MPC		0.76
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.85

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: rs104893637; hg19: chr2-20205934; COSMIC: COSV68100819; COSMIC: COSV68100819;