VCV001675209.5 - ClinVar

NM_002381.5(MATN3):c.400G>A (p.Glu134Lys)

Germline

Classification

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.

(2)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002381.5(MATN3):c.400G>A (p.Glu134Lys)

Variation ID: 1675209 Accession: VCV001675209.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p24.1 2: 20006134 (GRCh38) [ NCBI UCSC ] 2: 20205895 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Apr 8, 2022	Feb 14, 2024	Mar 8, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002381.5:c.400G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002372.1:p.Glu134Lys	missense
NC_000002.12:g.20006134C>T
NC_000002.11:g.20205895C>T
NG_008087.1:g.11561G>A

Protein change

E134K

Other names

Canonical SPDI

NC_000002.12:20006133:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs2103484088 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
MATN3		No evidence available	No evidence available	GRCh38 GRCh37	159	309

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Multiple epiphyseal dysplasia	not provided (1)	no classification provided	-	RCV002210945.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Mar 8, 2023	RCV003089110.3

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 Help 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 Help 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.
Likely pathogenic (Mar 08, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003524193.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 16287128‚ 14729835‚ 34092239 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MATN3 function (PMID: 16287128). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MATN3 protein function. ClinVar contains an entry for this variant (Variation ID: 1675209). This missense change has been observed in individuals with clinical features of multiple epiphyseal dysplasia (PMID: 14729835, 34092239; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 134 of the MATN3 protein (p.Glu134Lys). (less)
not provided (-)	no classification provided Method: literature only	Multiple epiphyseal dysplasia Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV002496177.2 First in ClinVar: Apr 08, 2022 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1123 BookShelf: NBK1123

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MATN3 function (PMID: 16287128). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MATN3 protein function. ClinVar contains an entry for this variant (Variation ID: 1675209). This missense change has been observed in individuals with clinical features of multiple epiphyseal dysplasia (PMID: 14729835, 34092239; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 134 of the MATN3 protein (p.Glu134Lys).

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Multiple Epiphyseal Dysplasia, Autosomal Dominant.	Adam MP	-	2024	PMID: 20301302
Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era.	Sabir AH	BMC medical genomics	2021	PMID: 34092239
Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A-domain and prevent secretion of mutant matrilin-3.	Cotterill SL	Human mutation	2005	PMID: 16287128
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 rs2103484088 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002381.5(MATN3):c.400G>A (p.Glu134Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2103484088 ...