ClinVar Genomic variation as it relates to human health
NM_001927.4(DES):c.1216C>T (p.Arg406Trp)
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_001927.4(DES):c.1216C>T (p.Arg406Trp)
Variation ID: 16826 Accession: VCV000016826.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 219421532 (GRCh38) [ NCBI UCSC ] 2: 220286254 (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 19, 2013 Apr 15, 2024 Feb 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001927.4:c.1216C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001918.3:p.Arg406Trp missense NC_000002.12:g.219421532C>T NC_000002.11:g.220286254C>T NG_008043.1:g.8156C>T LRG_380:g.8156C>T LRG_380t1:c.1216C>T P17661:p.Arg406Trp - Protein change
- R406W
- Other names
- p.R406W:CGG>TGG
- Canonical SPDI
- NC_000002.12:219421531:C:T
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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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DES | - | - |
GRCh38 GRCh37 |
1044 | 1088 |
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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Apr 12, 2023 | RCV000056781.18 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2024 | RCV000627795.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2023 | RCV001787806.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 4, 2020 | RCV001798009.9 |
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
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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
(Dec 01, 2015)
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criteria provided, single submitter
Method: research
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Desmin-related myofibrillar myopathy
Affected status: yes
Allele origin:
unknown
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Center for Genetic Medicine Research, Children's National Medical Center
Accession: SCV000265769.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(Sep 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043128.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
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Pathogenic
(Apr 12, 2023)
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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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GeneDx
Accession: SCV000235790.11
First in ClinVar: Jul 05, 2015 Last updated: Apr 23, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate abnormal filament assembly, in addition to microscopic analysis of cardiac and … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate abnormal filament assembly, in addition to microscopic analysis of cardiac and skeletal muscle revealing desmin-positive protein aggregates (Park et al., 2000; Chourbagi et al., 2011; Herrmann et al., 2020; Kubnek et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10717012, 35653365, 35626289, 35239206, 26807690, 10905661, 14991347, 27854218, 33673806, 32528171, 34712946, 32235386, 21262226, 33023321, 16376610) (less)
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Pathogenic
(Dec 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV000552187.10
First in ClinVar: Dec 06, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 406 of the DES protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 406 of the DES protein (p.Arg406Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with desmin myopathy (PMID: 10717012, 10905661, 14991347). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16826). 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 DES protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DES function (PMID: 21262226, 23425003). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 23, 2024)
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criteria provided, single submitter
Method: research
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Desmin-related myofibrillar myopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neurogenomics Lab, Neuroscience Institute, University Of Cape Town
Accession: SCV004708210.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Sequencing funding by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. PM2_supporting: This variant is absent from gnomAD v4 (adequate coverage >20x … (more)
Sequencing funding by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. PM2_supporting: This variant is absent from gnomAD v4 (adequate coverage >20x confirmed). PP3_moderate: REVEL score is 0.807. PM1 met: This variant occurs in exon 6 which encodes the C-terminal half of the coil 2 domain. Although disease-causing mutations spread over the entire desmin gene, they significantly cluster in exon 6. PS3_Supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product PS2_Moderate: Max 1 point awarded for 2 probands with de novo observations (paternity confirmed) and phenotype consistent with gene but not highly specific and high genetic heterogeneity. PS4 met: >=10 unrelated probands with consistent phenotype for disorder. (less)
Age: 30-39 years
Sex: male
Geographic origin: South Africa
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Pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002029247.3
First in ClinVar: Dec 12, 2021 Last updated: Apr 15, 2024 |
Comment:
This sequence change in DES is predicted to replace arginine with tryptophan at codon 406, p.(Arg406Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in DES is predicted to replace arginine with tryptophan at codon 406, p.(Arg406Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the intermediate filament rod domain. There is a large physicochemical difference between arginine and tryptophan. This variant is absent from gnomAD v2.1 and v3.1. This variant is frequently de novo, and has been identified as a de novo occurrence with confirmed parental relationships in at least four individuals with a severe and early-onset cardiomyopathy with/without myopathy. All reported individuals had muscle biopsy features consistent with a desmin myopathy (PMID: 10717012, 10905661, 14991347). A knock-in mouse-model of the orthologous variant developed a phenotype consistent with desmin myopathy, including desmin-positive protein aggregate pathology in skeletal muscle tissue (PMID: 33023321). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS2_VeryStrong, PS3, PM2_Supporting, PP3. (less)
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Pathogenic
(Apr 28, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000231642.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Mar 11, 2015)
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criteria provided, single submitter
Method: clinical testing
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Desmin-related myofibrillar myopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271350.2
First in ClinVar: Jun 28, 2015 Last updated: Dec 26, 2017 |
Comment:
The p.Arg406Trp variant in DES is absent from large populations sequenced by the Exome Aggregation Consortium (exac.broadinstitute.org/) but has been reported i n at least … (more)
The p.Arg406Trp variant in DES is absent from large populations sequenced by the Exome Aggregation Consortium (exac.broadinstitute.org/) but has been reported i n at least 5 individuals with clinical features of desminopathies, including con duction system disease +/-cardiomyopathy (DCM and RCM) and skeletal myopathy (sa me individuals reported in multiple papers; Dalakas 2000, Park 2000, Dagvadirj 2 004, Olive 2004, Wahbi 2012). In at least least 4 individuals the variant had oc curred de novo (paternity confirmed; same individuals reported in multiple paper s; Dalakas 2000, Park 2000, Dagvadirj 2004, Olive 2004). In vitro functional stu dies provide some evidence that the p.Arg406Trp variant impacts protein function (Park 2000, Chourbagi 2011). However, these types of assays sometimes do not ac curately represent biological function. In summary, this variant meets our crite ria to be classified as pathogenic for desminopathy with cardiac and skeletal my opathy involvement in an autosomal dominant manner (http://www.partners.org/pers onalizedmedicine/LMM) based upon absence from the general population and de novo occurrence. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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Desmin-related myofibrillar myopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149752.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Jun 01, 2000)
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no assertion criteria provided
Method: literature only
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MYOPATHY, MYOFIBRILLAR, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038599.3
First in ClinVar: Apr 04, 2013 Last updated: May 14, 2018 |
Comment on evidence:
In a sporadic case of cardiac and skeletal myopathy (MFM1; 601419), Park et al. (2000) demonstrated heterozygosity for an arg406-to-trp (R406W) mutation in the DES … (more)
In a sporadic case of cardiac and skeletal myopathy (MFM1; 601419), Park et al. (2000) demonstrated heterozygosity for an arg406-to-trp (R406W) mutation in the DES gene. The mutation was not found in the patient's father, mother, or sister. Alternative paternity was excluded. Haplotype analysis indicated that the patient's father was a germline mosaic for the desmin mutation. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Epithelial Biology; Institute of Medical Biology, Singapore
Accession: SCV000087894.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
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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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A case report of adolescent myofibrillar myopathy due to a de novo R406W pathogenic variant in desmin with symptoms of "hypertrophic cardiomyopathy". | Xiao H | Heliyon | 2024 | PMID: 38314304 |
The Myocardial Accumulation of Aggregated Desmin Protein in a Case of Desminopathy with a de novo DES p.R406W Mutation. | Takegami N | Internal medicine (Tokyo, Japan) | 2023 | PMID: 36792195 |
A Case Report of a Rare Heterozygous Variant in the Desmin Gene Associated With Hypertrophic Cardiomyopathy and Complete Atrioventricular Block. | Oka H | CJC open | 2021 | PMID: 34712946 |
Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy With Severe Intercalated Disc Derangement in Humans and in Knock-In Mice. | Herrmann H | Circulation | 2020 | PMID: 33023321 |
Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases. | Punetha J | Journal of neuromuscular diseases | 2016 | PMID: 27854218 |
Viral-mediated expression of desmin mutants to create mouse models of myofibrillar myopathy. | Joanne P | Skeletal muscle | 2013 | PMID: 23425003 |
Desminopathies: pathology and mechanisms. | Clemen CS | Acta neuropathologica | 2013 | PMID: 23143191 |
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 |
Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies. | Olivé M | Journal of the neurological sciences | 2004 | PMID: 15050448 |
A series of West European patients with severe cardiac and skeletal myopathy associated with a de novo R406W mutation in desmin. | Dagvadorj A | Journal of neurology | 2004 | PMID: 14991347 |
Sporadic cardiac and skeletal myopathy caused by a de novo desmin mutation. | Park KY | Clinical genetics | 2000 | PMID: 10905661 |
Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. | Dalakas MC | The New England journal of medicine | 2000 | PMID: 10717012 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DES | - | - | - | - |
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Text-mined citations for rs121913003 ...
HelpRecord last updated Apr 20, 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.