ClinVar Genomic variation as it relates to human health
NM_001927.4(DES):c.893C>T (p.Ser298Leu)
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.
Uncertain significance(8); Benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001927.4(DES):c.893C>T (p.Ser298Leu)
Variation ID: 66423 Accession: VCV000066423.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 219420652 (GRCh38) [ NCBI UCSC ] 2: 220285374 (GRCh37) [ NCBI UCSC ] 2: 219993618 (NCBI36) [ 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 20, 2013 Feb 28, 2024 Jan 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001927.4:c.893C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001918.3:p.Ser298Leu missense NC_000002.12:g.219420652C>T NC_000002.11:g.220285374C>T NG_008043.1:g.7276C>T LRG_380:g.7276C>T LRG_380t1:c.893C>T - Protein change
- S298L
- Other names
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- Canonical SPDI
- NC_000002.12:219420651: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 0.00008
The Genome Aggregation Database (gnomAD) 0.00014
Trans-Omics for Precision Medicine (TOPMed) 0.00017
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
Exome Aggregation Consortium (ExAC) 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
Help
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 |
1040 | 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
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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Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Aug 19, 2022 | RCV000056814.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 5, 2018 | RCV000171830.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 15, 2024 | RCV000466593.20 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jan 3, 2019 | RCV000735983.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001142372.11 | |
Benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001143228.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 8, 2023 | RCV003352761.1 |
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
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
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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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Uncertain significance
(Apr 05, 2018)
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criteria provided, single submitter
Method: research
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Primary dilated cardiomyopathy
Affected status: no
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Accession: SCV000055125.2
First in ClinVar: Jun 04, 2015 Last updated: May 05, 2018 |
Number of individuals with the variant: 1
Secondary finding: yes
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Uncertain significance
(Sep 11, 2015)
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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: SCV000335234.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Myofibrillar myopathy 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001302807.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1I
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001302806.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neurogenic scapuloperoneal syndrome, Kaeser type
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001303735.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(Mar 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001475073.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Uncertain significance
(Apr 11, 2019)
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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: SCV000491114.3
First in ClinVar: Oct 20, 2013 Last updated: Dec 15, 2018 |
Comment:
Reported previously in a patient with DCM but no reported myopathy; however segregation data were not provided (Taylor et al., 2007); Functional studies show disruption … (more)
Reported previously in a patient with DCM but no reported myopathy; however segregation data were not provided (Taylor et al., 2007); Functional studies show disruption of desmin filament assembly in the presence of the S298L variant (Taylor et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30564623, 23299917, 23861362, 17325244, 23143191, 22337857, 20474083, 27896284, 29926427) (less)
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Uncertain significance
(Aug 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004056210.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The p.S298L variant (also known as c.893C>T), located in coding exon 4 of the DES gene, results from a C to T substitution at nucleotide … (more)
The p.S298L variant (also known as c.893C>T), located in coding exon 4 of the DES gene, results from a C to T substitution at nucleotide position 893. The serine at codon 298 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in an individual with dilated cardiomyopathy (Taylor MR et al. Circulation, 2007 Mar;115:1244-51). In addition, this alteration has been detected in exome cohorts; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Aug 19, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003829066.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 15, 2024)
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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: SCV000552184.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 298 of the DES protein (p.Ser298Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 298 of the DES protein (p.Ser298Leu). This variant is present in population databases (rs62636491, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 17325244, 23861362). ClinVar contains an entry for this variant (Variation ID: 66423). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DES protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Jan 03, 2019)
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no assertion criteria provided
Method: clinical testing
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Cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000864165.1
First in ClinVar: Jan 13, 2019 Last updated: Jan 13, 2019 |
Sex: male
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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: SCV000087927.1
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 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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Is Desmin Propensity to Aggregate Part of its Protective Function? | Singh SR | Cells | 2020 | PMID: 32093415 |
Molecular insights into cardiomyopathies associated with desmin (DES) mutations. | Brodehl A | Biophysical reviews | 2018 | PMID: 29926427 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. | Andreasen C | European journal of human genetics : EJHG | 2013 | PMID: 23299917 |
Prevalence of desmin mutations in dilated cardiomyopathy. | Taylor MR | Circulation | 2007 | PMID: 17325244 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DES | - | - | - | - |
Text-mined citations for rs62636491 ...
HelpRecord last updated Mar 23, 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.