ClinVar Genomic variation as it relates to human health
NM_001927.4(DES):c.407T>A (p.Leu136His)
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.407T>A (p.Leu136His)
Variation ID: 44261 Accession: VCV000044261.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 219418869 (GRCh38) [ NCBI UCSC ] 2: 220283591 (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 Jun 1, 2016 Feb 28, 2024 Dec 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001927.4:c.407T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001918.3:p.Leu136His missense NC_000002.12:g.219418869T>A NC_000002.11:g.220283591T>A NG_008043.1:g.5493T>A LRG_380:g.5493T>A LRG_380t1:c.407T>A - Protein change
- L136H
- Other names
- p.L136H:CTC>CAC
- Canonical SPDI
- NC_000002.12:219418868:T:A
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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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0.00040 (A)
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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 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD) 0.00011
Exome Aggregation Consortium (ExAC) 0.00015
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 8, 2023 | RCV000037241.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 26, 2023 | RCV000528546.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 18, 2022 | RCV000618538.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV000735343.2 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 29, 2023 | RCV000726980.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 13, 2020 | RCV001798112.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 7, 2022 | RCV002504889.1 |
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
(-)
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criteria provided, single submitter
Method: clinical testing
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Pulmonary alveolar proteinosis
Congenital peripheral neuropathy Generalized hypotonia Infantile axial hypotonia Abnormal pulmonary interstitial morphology Myopathy Neonatal hypotonia Neonatal respiratory distress Proximal muscle weakness Proximal muscle weakness in upper limbs Respiratory distress Respiratory insufficiency due to muscle weakness Restrictive ventilatory defect Neonatal hypotonia Skeletal myopathy
Affected status: yes
Allele origin:
germline
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Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV000854497.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Sex: male
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Uncertain significance
(Jul 18, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060898.5
First in ClinVar: May 03, 2013 Last updated: Jan 07, 2017 |
Comment:
The Leu136His variant in DES has been identified by our laboratory in 1 individu al with DCM (LMM unpublished data). Data from large population studies … (more)
The Leu136His variant in DES has been identified by our laboratory in 1 individu al with DCM (LMM unpublished data). Data from large population studies is insuff icient to assess the frequency of this variant. Leucine (Leu) at position 136 is conserved in mammals, but not in more evolutionarily distant species. However, other computational analyses (biochemical amino acid properties, AlignGVGD, Poly Phen2, and SIFT) suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. Additional infor mation is needed to fully assess the clinical significance of this variant. (less)
Number of individuals with the variant: 2
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Uncertain significance
(Nov 18, 2022)
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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: SCV000736262.5
First in ClinVar: Apr 14, 2018 Last updated: Apr 15, 2023 |
Comment:
The p.L136H variant (also known as c.407T>A), located in coding exon 1 of the DES gene, results from a T to A substitution at nucleotide … (more)
The p.L136H variant (also known as c.407T>A), located in coding exon 1 of the DES gene, results from a T to A substitution at nucleotide position 407. The leucine at codon 136 is replaced by histidine, an amino acid with similar properties. This variant was reported in 2 individuals with dilated cardiomyopathy (DCM) and in an individual reported to have arrhythmogenic cardiomyopathy (Pugh TJ et al., Genet. Med. 2014 Aug; 16(8):601-8; Wilson KD et al., Circ. Res. 2015 Sep; 117(7):603-11; Campuzano O et al. EBioMedicine. 2020 Apr;54:102732). This variant has also been detected in cohorts with varying phenotypes including a pediatric exome sequencing cohort and probands with sudden death, long QT syndrome, and unspecified neuromuscular disorder; however, clinical details were limited (Proost D et al. J Mol Diagn. 2017 05;19(3):445-459; Ji J et al. Cold Spring Harb Mol Case Stud. 2019 04;5(2); Gonzalez-Quereda L et al. Genes (Basel). 2020 05;11(5)). This amino acid position is well 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 variant remains unclear. (less)
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Uncertain significance
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922856.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: DES c.407T>A (p.Leu136His) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. … (more)
Variant summary: DES c.407T>A (p.Leu136His) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 181860 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.407T>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy or Primary electrical disease (Pugh_2014, Wilson_2015, Proost_2017). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Aug 11, 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: SCV000704645.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Uncertain significance
(Jul 13, 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: SCV002043133.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
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Uncertain significance
(Apr 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurogenic scapuloperoneal syndrome, Kaeser type
Desmin-related myofibrillar myopathy Dilated cardiomyopathy 1I
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002814446.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jun 29, 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: SCV000235812.15
First in ClinVar: Jul 05, 2015 Last updated: Jul 08, 2023 |
Comment:
Reported in association with cardiomyopathy, primary electrical disease, and neuromuscular disease (Pugh et al., 2014; Wilson et al., 2015; Proost et al., 2017; Campuzano et … (more)
Reported in association with cardiomyopathy, primary electrical disease, and neuromuscular disease (Pugh et al., 2014; Wilson et al., 2015; Proost et al., 2017; Campuzano et al., 2020; Gonzalez-Quereda L 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: 32268277, 28341588, 30564623, 24503780, 32403337, 33823640, 30755392, 26265630, 36497166, 26807690) (less)
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Uncertain significance
(Nov 01, 2019)
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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: SCV003829039.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 26, 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: SCV000654174.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 136 of the DES protein (p.Leu136His). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 136 of the DES protein (p.Leu136His). This variant is present in population databases (rs397516695, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of DES-related conditions (PMID: 26265630, 28341588, 30755392, 32403337). ClinVar contains an entry for this variant (Variation ID: 44261). 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%. 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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Uncertain significance
(Dec 07, 2014)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280071.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below we consider this variant a variant of uncertain significance. This is a novel variant. This is a non-conservative amino acid change of a hydrophobic leucine to a hydrophilic histidine. The leucine at codon 136 is well conserved across evolution (except in chickens). PolyPhen2 predicts the variant to be probably damaging. Mutation Taster predicts this variant to be disease-causing. The leucine at codon 136 is conserved across species, as are neighboring amino acids. In total the variant has not been seen in ~6,700 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 136 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/30/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 9/30/13). (less)
Number of individuals with the variant: 1
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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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Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. | Gonzalez-Quereda L | Genes | 2020 | PMID: 32403337 |
Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes. | Campuzano O | EBioMedicine | 2020 | PMID: 32268277 |
A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants. | Ji J | Cold Spring Harbor molecular case studies | 2019 | PMID: 30755392 |
Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. | Proost D | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28341588 |
A Rapid, High-Quality, Cost-Effective, Comprehensive and Expandable Targeted Next-Generation Sequencing Assay for Inherited Heart Diseases. | Wilson KD | Circulation research | 2015 | PMID: 26265630 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DES | - | - | - | - |
Text-mined citations for rs397516695 ...
HelpRecord last updated Mar 17, 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.