ClinVar Genomic variation as it relates to human health
NM_002381.5(MATN3):c.359C>T (p.Thr120Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002381.5(MATN3):c.359C>T (p.Thr120Met)
Variation ID: 65664 Accession: VCV000065664.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p24.1 2: 20006175 (GRCh38) [ NCBI UCSC ] 2: 20205936 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 2, 2013 Apr 15, 2024 Jun 24, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002381.5:c.359C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002372.1:p.Thr120Met missense NM_002381.5:c.[359C>T] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000002.12:g.20006175G>A NC_000002.11:g.20205936G>A NG_008087.1:g.11520C>T O15232:p.Thr120Met - Protein change
- T120M
- Other names
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- Canonical SPDI
- NC_000002.12:20006174:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MATN3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
156 | 304 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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- | RCV000055878.7 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 24, 2021 | RCV001093350.22 | |
Pathogenic (2) |
criteria provided, single submitter
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- | RCV001375669.4 | |
not provided (1) |
no classification provided
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- | RCV002054898.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jan 08, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449729.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 2
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Multiple epiphyseal dysplasia type 5
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073078.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.T120M in MATN3 (NM_002381.5) has been reported in multiple affected individuals and shows incomplete penetrance (Mabuchi A et al; Jackson GC et … (more)
The missense variant p.T120M in MATN3 (NM_002381.5) has been reported in multiple affected individuals and shows incomplete penetrance (Mabuchi A et al; Jackson GC et al; Kim OH et al). It has been submitted to ClinVar as Pathogenic.The p.T120M variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.T120M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 120 of MATN3 is conserved in all mammalian species. The nucleotide c.359 in MATN3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic (less)
Clinical Features:
Proximal muscle weakness (present) , Lower limb pain (present) , Knee pain (present) , Gowers sign (present) , Scoliosis (present) , Genu valgum (present) , … (more)
Proximal muscle weakness (present) , Lower limb pain (present) , Knee pain (present) , Gowers sign (present) , Scoliosis (present) , Genu valgum (present) , Multiple epiphyseal dysplasia (present) , Limb-girdle muscular dystrophy (present) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Spondyloepimetaphyseal dysplasia, matrilin-3 type
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100565.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The missense variant p.T120M in MATN3 (NM_002381.5) has been reported in multiple affected individuals and shows incomplete penetrance (Mabuchi A et al,Jackson GC et al,Kim … (more)
The missense variant p.T120M in MATN3 (NM_002381.5) has been reported in multiple affected individuals and shows incomplete penetrance (Mabuchi A et al,Jackson GC et al,Kim OH et al). It has been submitted to ClinVar as Pathogenic. The p.T120M variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.T120M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 120 of MATN3 is conserved in all mammalian species. The nucleotide c.359 in MATN3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Hypoparathyroidism (present)
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Pathogenic
(Jun 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001591723.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine with methionine at codon 120 of the MATN3 protein (p.Thr120Met). The threonine residue is highly conserved and there is a … (more)
This sequence change replaces threonine with methionine at codon 120 of the MATN3 protein (p.Thr120Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with multiple epiphyseal dysplasia (PMID: 14729835, 21965141, 15459972). It has been observed to segregate with disease in related individuals; however it has also been observed in reportedly unaffected family members, suggesting reduced penetrance. ClinVar contains an entry for this variant (Variation ID: 65664). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250287.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 01, 2004)
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no assertion criteria provided
Method: literature only
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EPIPHYSEAL DYSPLASIA, MULTIPLE, 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001572595.1
First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
Comment on evidence:
Multiple Epiphyseal Dysplasia 5 In an 8-year-old girl (family 3) with multiple epiphyseal dysplasia-5 (EDM5; 607078), Jackson et al. (2004) identified compound heterozygous mutations in … (more)
Multiple Epiphyseal Dysplasia 5 In an 8-year-old girl (family 3) with multiple epiphyseal dysplasia-5 (EDM5; 607078), Jackson et al. (2004) identified compound heterozygous mutations in the MATN3 gene: c.359C-T transition in exon 2, predicted to result in a thr120-to-met (T120M) substitution, and a c.908C-T transition in exon 3, predicted to result in a thr303-to-met (T303M; 602109.0009) substitution. Analysis of DNA from her apparently unaffected mother demonstrated the presence of T120M but not T303M. The father's DNA was not available for study. Spondyloepimetaphyseal Dysplasia, Borochowitz-Cormier-Daire Type In a 22-month-old Indian child with spondyloepimetaphyseal dysplasia of the Borochowitz-Cormier-Daire type (SEMDBCD; 608728), Shyamasundar et al. (2020) identified a homozygous c.359C-T transition in exon 2 of the MATN3 gene, resulting in a thr120-to-met (T120M) substitution. The mutation, which was found by exome sequencing, was present in heterozygous state in the parents. The mutation is located in the beta sheet of the single-A domain of matrilin-3, which suggests a deleterious effect on the folding and function of the protein. (less)
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Pathogenic
(Jan 01, 2004)
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no assertion criteria provided
Method: literature only
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SPONDYLOEPIMETAPHYSEAL DYSPLASIA, BOROCHOWITZ-CORMIER-DAIRE TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001572596.1
First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
Comment on evidence:
Multiple Epiphyseal Dysplasia 5 In an 8-year-old girl (family 3) with multiple epiphyseal dysplasia-5 (EDM5; 607078), Jackson et al. (2004) identified compound heterozygous mutations in … (more)
Multiple Epiphyseal Dysplasia 5 In an 8-year-old girl (family 3) with multiple epiphyseal dysplasia-5 (EDM5; 607078), Jackson et al. (2004) identified compound heterozygous mutations in the MATN3 gene: c.359C-T transition in exon 2, predicted to result in a thr120-to-met (T120M) substitution, and a c.908C-T transition in exon 3, predicted to result in a thr303-to-met (T303M; 602109.0009) substitution. Analysis of DNA from her apparently unaffected mother demonstrated the presence of T120M but not T303M. The father's DNA was not available for study. Spondyloepimetaphyseal Dysplasia, Borochowitz-Cormier-Daire Type In a 22-month-old Indian child with spondyloepimetaphyseal dysplasia of the Borochowitz-Cormier-Daire type (SEMDBCD; 608728), Shyamasundar et al. (2020) identified a homozygous c.359C-T transition in exon 2 of the MATN3 gene, resulting in a thr120-to-met (T120M) substitution. The mutation, which was found by exome sequencing, was present in heterozygous state in the parents. The mutation is located in the beta sheet of the single-A domain of matrilin-3, which suggests a deleterious effect on the folding and function of the protein. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Multiple epiphyseal dysplasia
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000086881.3
First in ClinVar: Oct 02, 2013 Last updated: Oct 01, 2022 |
Comment:
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 … (more)
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]. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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MATN3 Mutation Causing Spondyloepimetaphyseal Dysplasia. | Shyamasundar LG | Indian journal of pediatrics | 2020 | PMID: 31724101 |
Multiple Epiphyseal Dysplasia, Autosomal Dominant. | Adam MP | - | 2019 | PMID: 20301302 |
Revisit of multiple epiphyseal dysplasia: ethnic difference in genotypes and comparison of radiographic features linked to the COMP and MATN3 genes. | Kim OH | American journal of medical genetics. Part A | 2011 | PMID: 21965141 |
Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia. | Mabuchi A | Human mutation | 2004 | PMID: 15459972 |
Missense mutations in the beta strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia. | Jackson GC | Journal of medical genetics | 2004 | PMID: 14729835 |
Text-mined citations for rs397515546 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.