ClinVar Genomic variation as it relates to human health
NM_001927.4(DES):c.1049G>C (p.Arg350Pro)
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.1049G>C (p.Arg350Pro)
Variation ID: 16835 Accession: VCV000016835.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 219421365 (GRCh38) [ NCBI UCSC ] 2: 220286087 (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 Apr 4, 2013 Apr 15, 2024 Sep 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001927.4:c.1049G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001918.3:p.Arg350Pro missense NC_000002.12:g.219421365G>C NC_000002.11:g.220286087G>C NG_008043.1:g.7989G>C LRG_380:g.7989G>C LRG_380t1:c.1049G>C LRG_380p1:p.Arg350Pro P17661:p.Arg350Pro - Protein change
- R350P
- Other names
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- Canonical SPDI
- NC_000002.12:219421364:G:C
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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
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
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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 (1) |
no assertion criteria provided
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Jun 1, 2007 | RCV000018329.24 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2021 | RCV000056767.22 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 26, 2023 | RCV000651542.10 |
Submissions - Germline
Classification
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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
(Dec 05, 2017)
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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: SCV000858481.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Sep 26, 2023)
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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:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004100749.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Criteria applied: PS3,PP1_STR,PM2_SUP,PP3
Clinical Features:
Myopathy (present) , EMG: myopathic abnormalities (present)
Sex: female
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Pathogenic
(Nov 15, 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: SCV000773396.6
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
Experimental studies have shown that this missense change affects DES function (PMID: 15800015, 20448486, 25394388, 27393313). Advanced modeling of protein sequence and biophysical properties (such … (more)
Experimental studies have shown that this missense change affects DES function (PMID: 15800015, 20448486, 25394388, 27393313). 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. ClinVar contains an entry for this variant (Variation ID: 16835). This missense change has been observed in individual(s) with DES-related myofibrillar myopathy (PMID: 15800015, 17439987). 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 arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 350 of the DES protein (p.Arg350Pro). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248941.18
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 4
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448105.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Progressive distal muscular atrophy (present) , Hypertonia (present) , Sick sinus syndrome (present) , Coronary artery atherosclerosis (present) , Sensory neuropathy (present)
Sex: male
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Pathogenic
(Jun 01, 2007)
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no assertion criteria provided
Method: literature only
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SCAPULOPERONEAL SYNDROME, NEUROGENIC, KAESER TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038608.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In the large, multigenerational kindred with scapuloperoneal weakness and atrophy (SCPNK; 181400) originally described by Kaeser (1964, 1965), Walter et al. (2007) detected a heterozygous … (more)
In the large, multigenerational kindred with scapuloperoneal weakness and atrophy (SCPNK; 181400) originally described by Kaeser (1964, 1965), Walter et al. (2007) detected a heterozygous 1049G-C transversion in the DES gene that resulted in an arg350-to-pro (R350P) amino acid substitution in all affected members. This mutation had been described by Bar et al. (2005) in a family with mixed distal myopathy/limb girdle phenotype, presented as family 4 by Walter et al. (2007). Bar et al. (2005) reported the effects of the R350P mutation, which resides in conserved coil 2B domain of the alpha-helical coiled-coil desmin rod domain. Transfection studies showed that R350P-mutant desmin was incapable of de novo formation of a desmin intermediate filament network in vimentin (193060)-free cells, and that it disrupted the endogenous vimentin cytoskeleton in fibroblasts. In vitro studies revealed that the assembly process of R350P-mutant desmin was already disturbed at the unit length filament level, and that further association reactions generated huge, tightly packed protein aggregates. A ratio of 1:3 (R350P to wildtype) was sufficient to effectively block the normal polymerization process of desmin intermediate filaments. Bar et al. (2005) concluded that the R350P mutation exerted a dominant-negative effect on the ordered lateral arrangement of desmin subunits. (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: SCV000087880.1
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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Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue. | Winter L | Acta neuropathologica | 2016 | PMID: 27393313 |
The toxic effect of R350P mutant desmin in striated muscle of man and mouse. | Clemen CS | Acta neuropathologica | 2015 | PMID: 25394388 |
Divergent molecular effects of desmin mutations on protein assembly in myofibrillar myopathy. | Levin J | Journal of neuropathology and experimental neurology | 2010 | PMID: 20448486 |
Scapuloperoneal syndrome type Kaeser and a wide phenotypic spectrum of adult-onset, dominant myopathies are associated with the desmin mutation R350P. | Walter MC | Brain : a journal of neurology | 2007 | PMID: 17439987 |
Pathogenic effects of a novel heterozygous R350P desmin mutation on the assembly of desmin intermediate filaments in vivo and in vitro. | Bär H | Human molecular genetics | 2005 | PMID: 15800015 |
Scapuloperoneal muscular atrophy. | Kaeser HE | Brain : a journal of neurology | 1965 | PMID: 5828910 |
[FAMILIAL SCAPULOPERONEAL MUSCULAR ATROPHY]. | KAESER HE | Deutsche Zeitschrift fur Nervenheilkunde | 1964 | PMID: 14326018 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DES | - | - | - | - |
Text-mined citations for rs57965306 ...
HelpRecord last updated Apr 15, 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.