ClinVar Genomic variation as it relates to human health
NM_001927.4(DES):c.1285C>T (p.Arg429Ter)
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.1285C>T (p.Arg429Ter)
Variation ID: 177872 Accession: VCV000177872.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 219423817 (GRCh38) [ NCBI UCSC ] 2: 220288539 (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 Jan 31, 2015 Feb 28, 2024 Jun 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001927.4:c.1285C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001918.3:p.Arg429Ter nonsense NC_000002.12:g.219423817C>T NC_000002.11:g.220288539C>T NG_008043.1:g.10441C>T LRG_380:g.10441C>T LRG_380t1:c.1285C>T - Protein change
- R429*
- Other names
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- Canonical SPDI
- NC_000002.12:219423816: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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 |
- | 1086 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Jun 12, 2013 | RCV000154519.4 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jun 30, 2023 | RCV000327525.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2022 | RCV001059931.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 21, 2022 | RCV002469028.1 |
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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Pathogenic
(Aug 04, 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: SCV000344024.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Likely pathogenic
(Jun 12, 2013)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
Desmin-related myofibrillar myopathy Neuromuscular disease (Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204191.4
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Comment:
The Arg429X variant in DES has not been previously reported in individuals with isolated cardiomyopathy, but has been identified in 1/8600 European American chr omosomes … (more)
The Arg429X variant in DES has not been previously reported in individuals with isolated cardiomyopathy, but has been identified in 1/8600 European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS/; dbSNP rs150974575). It has also been identified by ou r laboratory in 1 family, where it was present in trans with a second DES varian t (frameshift) in 2 individuals with features consistent with a desminopathy. Ea ch unaffected parent carried 1 of the variants, which is suggestive of recessive inheritance. This variant leads to a premature termination codon at position 42 9, which is predicted to lead to a truncated or absent protein. The spectrum of reported DES variants includes several similar variants (nonsense, splice, frame shift; Park 2000, Schroeder 2003, Dunand 2009, Hong 2011, Wahbi 2011). While one of these variants (Dunand 2009) showed clear autosomal dominant inheritance, th is could not be conclusively established for the other variants. In summary, thi s variant is likely to cause disease when present with a second DES variant, but additional studies are needed to fully establish its clinical significance. (less)
Number of individuals with the variant: 5
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Pathogenic
(Nov 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Primary familial dilated cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766183.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: DES c.1285C>T (p.Arg429X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: DES c.1285C>T (p.Arg429X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Truncations downstream of this position have been reported in association with cardiomyopathy in HGMD. The variant allele was found at a frequency of 1.2e-05 in 251480 control chromosomes. c.1285C>T has been reported in the literature in individuals affected with skeletal myopathy and cardiomyopathy, in addition to other features, in two unrelated individuals who also carried second truncating DES mutations, and in both cases the individuals had a family history of the phenotype (McLaughlin_2013, Zhu_2015). While DES variants are most commonly autosomal dominant or de novo dominant missense mutations, a few rare cases of autosomal recessive desminopathy have been described ranging from severe infantile to adult-onset, with variable phenotypic presentations affecting skeletal, cardiac and smooth muscle. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 30, 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: SCV003840810.2
First in ClinVar: Mar 18, 2023 Last updated: Aug 05, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33874732, 24503780, 31402444, 27532257, 25590979, 23815709) (less)
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Pathogenic
(Jan 01, 2022)
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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: SCV001224586.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 177872). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 177872). This premature translational stop signal has been observed in individual(s) with autosomal recessive DES-related conditions (PMID: 23815709, 25590979). This variant is present in population databases (rs150974575, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg429*) in the DES gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DES are known to be pathogenic (PMID: 23575897). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971763.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929712.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954514.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy. | Goli R | Circulation | 2021 | PMID: 33874732 |
Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. | Zhu X | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25590979 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy. | McLaughlin HM | BMC medical genetics | 2013 | PMID: 23815709 |
Recessive desmin-null muscular dystrophy with central nuclei and mitochondrial abnormalities. | Henderson M | Acta neuropathologica | 2013 | PMID: 23575897 |
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 |
A series of Chinese patients with desminopathy associated with six novel and one reported mutations in the desmin gene. | Hong D | Neuropathology and applied neurobiology | 2011 | PMID: 20696008 |
Confirmation that abnormal desmin accumulation and migration are due to a desmin gene mutation in a familial cardiomyopathy and distal myopathy. | Dunand M | Neuromuscular disorders : NMD | 2009 | PMID: 19716701 |
Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. | Goldfarb LG | The Journal of clinical investigation | 2009 | PMID: 19587455 |
Desmin myopathy. | Goldfarb LG | Brain : a journal of neurology | 2004 | PMID: 14724127 |
On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria. | Schröder R | Human molecular genetics | 2003 | PMID: 12620971 |
Desmin splice variants causing cardiac and skeletal myopathy. | Park KY | Journal of medical genetics | 2000 | PMID: 11073539 |
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 rs150974575 ...
HelpRecord last updated Apr 06, 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.