VCV000014002.37 - ClinVar

NM_018834.6(MATR3):c.254C>G (p.Ser85Cys)

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.

(7)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_018834.6(MATR3):c.254C>G (p.Ser85Cys)

Variation ID: 14002 Accession: VCV000014002.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q31.2 5: 139307669 (GRCh38) [ NCBI UCSC ] 5: 138643358 (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	Oct 31, 2013	Oct 20, 2024	Jun 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_018834.6:c.254C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_061322.2:p.Ser85Cys	missense
NM_001194954.2:c.254C>G	NP_001181883.1:p.Ser85Cys	missense
NM_001194955.2:c.254C>G	NP_001181884.1:p.Ser85Cys	missense
NM_001194956.2:c.49-7006C>G		intron variant
NM_001282278.2:c.-102-7006C>G		intron variant
NM_199189.3:c.254C>G	NP_954659.1:p.Ser85Cys	missense
NC_000005.10:g.139307669C>G
NC_000005.9:g.138643358C>G
NG_012846.1:g.38567C>G
	P43243:p.Ser85Cys

... more HGVS ... less HGVS

Protein change

S85C

Other names

Canonical SPDI

NC_000005.10:139307668:C:G

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

ClinGen: CA123688 UniProtKB: P43243#VAR_063421 UniProtKB/Swiss-Prot: VAR_063421 OMIM: 164015.0001 dbSNP: rs121434591 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.
MATR3		-	-	GRCh38 GRCh37	429	552

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.
Amyotrophic lateral sclerosis type 21	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 26, 2023	RCV000015039.45
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 20, 2017	RCV000517083.24

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.
Pathogenic (Jun 20, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000614054.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (9) PubMed: 19344878‚ 26528920‚ 24686783‚ 25677933‚ 25952333‚ 25185957‚ 26493020‚ 26780671‚ 25154462
Pathogenic (Dec 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Amyotrophic lateral sclerosis type 21 Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428685.1 First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020	Number of individuals with the variant: 1
Pathogenic (Dec 10, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Amyotrophic lateral sclerosis type 21 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017223.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jun 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Amyotrophic lateral sclerosis type 21 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000653847.4 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 24686783‚ 9837826‚ 19344878‚ 25154462‚ 25677933‚ 25952333 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MATR3 function (PMID: 24686783). Advanced modeling … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MATR3 function (PMID: 24686783). 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 MATR3 protein function. ClinVar contains an entry for this variant (Variation ID: 14002). This missense change has been observed in individual(s) with autosomal dominant distal myopathy with variable vocal cord weakness, pharyngeal weakness and respiratory failure (PMID: 9837826, 19344878, 24686783, 25154462, 25677933, 25952333). 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 serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 85 of the MATR3 protein (p.Ser85Cys). (less)
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248350.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Nov 01, 2014)	no assertion criteria provided Method: literature only	AMYOTROPHIC LATERAL SCLEROSIS 21 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035295.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 12, 2021	Publications: PubMed (4) PubMed: 9837826‚ 24686783‚ 19344878‚ 25154462 Comment on evidence: In affected members of a North American family originally diagnosed with distal myopathy with vocal cord and pharyngeal weakness (Feit et al., 1998), but later … (more) In affected members of a North American family originally diagnosed with distal myopathy with vocal cord and pharyngeal weakness (Feit et al., 1998), but later reclassified as having amyotrophic lateral sclerosis (ALS21; 606070) (Johnson et al., 2014), Senderek et al. (2009) identified a heterozygous 254C-G transversion in exon 2 of the MATR3 gene, resulting in a ser85-to-cys (S85C) substitution. Senderek et al. (2009) found the same heterozygous mutation in an unrelated Bulgarian family with a similar disorder. Johnson et al. (2014) found that the S85C mutation increased the interaction of mutant MATR3 with TARDBP (605078) compared to wildtype. S85C was also expressed at a lower steady-state level compared to wildtype and to other MATR3 variants, suggesting a structural effect of the mutation. Mutant S85C coaggregated with TARDBP in skeletal muscle from a patient carrying the mutation. Muller et al. (2014) reported 16 patients from 6 unrelated German families with the S85C MATR3 mutation. Haplotype analysis indicated a founder effect that was distinct from the haplotype in the families reported by Johnson et al. (2014). Muller et al. (2014) concluded that the phenotype in the German families was more consistent with distal myopathy than ALS. (less)
likely pathogenic (-)	no assertion criteria provided Method: not provided	Myopathy, distal, 2 Affected status: not provided Allele origin: not provided	UniProtKB/Swiss-Prot Accession: SCV000091147.1 First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013	Comment: Converted during submission to Likely pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MATR3 function (PMID: 24686783). 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 MATR3 protein function. ClinVar contains an entry for this variant (Variation ID: 14002). This missense change has been observed in individual(s) with autosomal dominant distal myopathy with variable vocal cord weakness, pharyngeal weakness and respiratory failure (PMID: 9837826, 19344878, 24686783, 25154462, 25677933, 25952333). 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 serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 85 of the MATR3 protein (p.Ser85Cys).

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
New ALS-Related Genes Expand the Spectrum Paradigm of Amyotrophic Lateral Sclerosis.	Sabatelli M	Brain pathology (Zurich, Switzerland)	2016	PMID: 26780671
Replication study of MATR3 in familial and sporadic amyotrophic lateral sclerosis.	Leblond CS	Neurobiology of aging	2016	PMID: 26493020
Re-evaluation of the phenotype caused by the common MATR3 p.Ser85Cys mutation in a new family.	Palmio J	Journal of neurology, neurosurgery, and psychiatry	2016	PMID: 25952333
Subcellular Localization of Matrin 3 Containing Mutations Associated with ALS and Distal Myopathy.	Gallego-Iradi MC	PloS one	2015	PMID: 26528920
Impairment of respiratory function in late-onset distal myopathy due to MATR3 Mutation.	Kraya T	Muscle & nerve	2015	PMID: 25677933
Clinicopathological features of the first Asian family having vocal cord and pharyngeal weakness with distal myopathy due to a MATR3 mutation.	Yamashita S	Neuropathology and applied neurobiology	2015	PMID: 25185957
Phenotype of matrin-3-related distal myopathy in 16 German patients.	Müller TJ	Annals of neurology	2014	PMID: 25154462
Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis.	Johnson JO	Nature neuroscience	2014	PMID: 24686783
Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3.	Senderek J	American journal of human genetics	2009	PMID: 19344878
Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31.	Feit H	American journal of human genetics	1998	PMID: 9837826

Text-mined citations for rs121434591 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_018834.6(MATR3):c.254C>G (p.Ser85Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121434591 ...