VCV000016834.36 - ClinVar

NM_001927.4(DES):c.1325C>T (p.Thr442Ile)

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.

(5)

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_001927.4(DES):c.1325C>T (p.Thr442Ile)

Variation ID: 16834 Accession: VCV000016834.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 219425699 (GRCh38) [ NCBI UCSC ] 2: 220290421 (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 19, 2013	Oct 20, 2024	Dec 10, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_001927.4:c.1325C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001918.3:p.Thr442Ile	missense
NC_000002.12:g.219425699C>T
NC_000002.11:g.220290421C>T
NG_008043.1:g.12323C>T
LRG_380:g.12323C>T
LRG_380t1:c.1325C>T	LRG_380p1:p.Thr442Ile
	P17661:p.Thr442Ile

... more HGVS ... less HGVS

Protein change

T442I

Other names

Canonical SPDI

NC_000002.12:219425698: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

ClinGen: CA217036 UniProtKB: P17661#VAR_042459 OMIM: 125660.0015 dbSNP: rs121913005 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.
DES		-	-	GRCh38 GRCh37	1065	1111

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.
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 1, 2018	RCV000056784.32
Desmin-related myofibrillar myopathy	Pathogenic (2)	criteria provided, single submitter	Dec 10, 2018	RCV000811753.16

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 (Dec 10, 2018)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Desmin-related myofibrillar myopathy Desmin-related myofibrillar myopathy Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000952036.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 17221859‚ 21262226‚ 22153487‚ 18653338‚ 22215463 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects¬†desmin assembly and aggregate formation¬†(PMID: 17221859, 21262226). … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects¬†desmin assembly and aggregate formation¬†(PMID: 17221859, 21262226). This variant has been reported to segregate with autosomal dominant cardiac and skeletal myopathy in families (PMID: 17221859, 22153487) and has been reported in several individuals affected with autosomal dominant myofibrillar myopathy and desmin-related myopathy (PMID:18653338, 22215463). ClinVar contains an entry for this variant (Variation ID: 16834). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 442 of the DES protein (p.Thr442Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. (less)
Pathogenic (May 21, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331912.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 17221859‚ 22153487‚ 22215463 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DES Number of individuals with the variant: 4 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Oct 01, 2018)	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: SCV001248942.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Apr 01, 2007)	no assertion criteria provided Method: literature only	MYOPATHY, MYOFIBRILLAR, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038607.4 First in ClinVar: Apr 04, 2013 Last updated: May 14, 2018	Publications: PubMed (1) PubMed: 17221859 Comment on evidence: In 3 affected members of a French family with autosomal dominant myofibrillar myopathy-1 (MFM1; 601419), Bar et al. (2007) identified a 1325C-T transition in the … (more) In 3 affected members of a French family with autosomal dominant myofibrillar myopathy-1 (MFM1; 601419), Bar et al. (2007) identified a 1325C-T transition in the DES gene, resulting in a thr442-to-ile (T442I) substitution in the C-terminal tail domain. The proband had onset of proximal and distal lower limb weakness and dyspnea on exertion at age 35 years, followed by proximal upper limb weakness a year later. He had increased serum creatine kinase and became wheelchair-bound at age 44 years. He underwent tracheostomy for nocturnal ventilatory assistance at age 46 years. A year later he had a pacemaker implanted for bradyarrhythmia. Of note, the patient had repetitive episodes of diarrhea and constipation during the disease course, indicating smooth muscle involvement. His mother and 2 maternal aunts died of heart failure. A sporadic patient from Canada, who also had the mutation, developed distal muscle weakness at age 33 years and cardiomyopathy approximately 5 years later. Functional expression studies in vitro and in cell culture showed that the T442I mutant protein assembled into filaments with abnormal viscometric properties. Coexpression with wildtype desmin showed a severe disturbance of filament formation and filament-filament interaction, indicating an inability for the mutant and wildtype proteins to form mixed filaments. (less)
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Epithelial Biology; Institute of Medical Biology, Singapore Accession: SCV000087897.1 First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects¬†desmin assembly and aggregate formation¬†(PMID: 17221859, 21262226). This variant has been reported to segregate with autosomal dominant cardiac and skeletal myopathy in families (PMID: 17221859, 22153487) and has been reported in several individuals affected with autosomal dominant myofibrillar myopathy and desmin-related myopathy (PMID:18653338, 22215463). ClinVar contains an entry for this variant (Variation ID: 16834). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 442 of the DES protein (p.Thr442Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine.

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
Recurrent and founder mutations in the Netherlands: the cardiac phenotype of DES founder mutations p.S13F and p.N342D.	van Spaendonck-Zwarts KY	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2012	PMID: 22215463
High cardiovascular morbidity and mortality in myofibrillar myopathies due to DES gene mutations: a 10-year longitudinal study.	Wahbi K	Neuromuscular disorders : NMD	2012	PMID: 22153487
Desmin mutations in the terminal consensus motif prevent synemin-desmin heteropolymer filament assembly.	Chourbagi O	Experimental cell research	2011	PMID: 21262226
Electron microscopy in myofibrillar myopathies reveals clues to the mutated gene.	Claeys KG	Neuromuscular disorders : NMD	2008	PMID: 18653338
Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies.	Bär H	Human mutation	2007	PMID: 17221859
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DES	-	-	-	-

Text-mined citations for rs121913005 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001927.4(DES):c.1325C>T (p.Thr442Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913005 ...