ClinVar Genomic variation as it relates to human health
NM_001927.4(DES):c.1255C>T (p.Pro419Ser)
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.1255C>T (p.Pro419Ser)
Variation ID: 39718 Accession: VCV000039718.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 219423787 (GRCh38) [ NCBI UCSC ] 2: 220288509 (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 Feb 28, 2024 Dec 12, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001927.4:c.1255C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001918.3:p.Pro419Ser missense NC_000002.12:g.219423787C>T NC_000002.11:g.220288509C>T NG_008043.1:g.10411C>T LRG_380:g.10411C>T LRG_380t1:c.1255C>T P17661:p.Pro419Ser - Protein change
- P419S
- Other names
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- Canonical SPDI
- NC_000002.12:219423786: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 | - |
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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Likely pathogenic (2) |
criteria provided, single submitter
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Mar 7, 2016 | RCV000056783.12 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 12, 2019 | RCV000817811.18 |
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 12, 2019)
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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: SCV000958394.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change forms filaments and does not induce aggregation … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change forms filaments and does not induce aggregation in cell lines (PMID: 23032110). This variant has been observed to segregate with autosomal dominant desminopathies in several families (PMID:17418574, 22153487, 22395865, 26431784). ClinVar contains an entry for this variant (Variation ID: 39718). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 419 of the DES protein (p.Pro419Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. (less)
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Likely pathogenic
(Mar 07, 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: SCV000336776.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(-)
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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:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100543.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The missense variant p.P419S in DES (NM_001927.4) has been previously reported in multiple patients with autosomal dominant desminopathies (Olivé M et al,Wahbi K et al). … (more)
The missense variant p.P419S in DES (NM_001927.4) has been previously reported in multiple patients with autosomal dominant desminopathies (Olivé M et al,Wahbi K et al). Functional studies reveal a damaging effect (Brodehl A et al). The variant has been submitted to ClinVar as Pathogenic.The p.P419S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and serine. The p.P419S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 419 of DES is conserved in all mammalian species. The nucleotide c.1255 in DES is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Myopathy (present) , Rimmed vacuoles (present) , Limb-girdle muscular dystrophy (present) , Muscular dystrophy (present)
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Pathogenic
(Sep 01, 2012)
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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: SCV000056695.3
First in ClinVar: Apr 04, 2013 Last updated: May 14, 2018 |
Comment on evidence:
In 7 affected members of a large Swedish family with autosomal dominant myofibrillary myopathy-1 with arrhythmogenic right ventricular cardiomyopathy (MFM1; 601419) originally reported by Melberg … (more)
In 7 affected members of a large Swedish family with autosomal dominant myofibrillary myopathy-1 with arrhythmogenic right ventricular cardiomyopathy (MFM1; 601419) originally reported by Melberg et al. (1999), Hedberg et al. (2012) identified a heterozygous 1255C-T transition in exon 7 of the DES gene, resulting in a pro419-to-ser (P419S) substitution in the tail region of desmin. The mutation was identified by exome sequencing and confirmed by Sanger sequencing. The phenotype in this family was characterized by variable muscle weakness associated with myopathic changes and desmin accumulation on muscle biopsy. Three patients had arrhythmogenic right ventricular cardiomyopathy, resulting in death. Initial mapping studies on this family by Melberg et al. (1999) had found linkage to chromosome 10q22, and the locus was formerly designated in OMIM as ARVD7. (less)
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Pathogenic
(Feb 11, 2019)
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no assertion criteria provided
Method: research
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Desmin-related myofibrillar myopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea
Accession: SCV000882769.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
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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: SCV000087896.1
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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Functional characterization of desmin mutant p.P419S. | Brodehl A | European journal of human genetics : EJHG | 2013 | PMID: 23032110 |
Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation. | Hedberg C | European journal of human genetics : EJHG | 2012 | PMID: 22395865 |
Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene. | Olivé M | Neuromuscular disorders : NMD | 2007 | PMID: 17418574 |
Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q. | Melberg A | Annals of neurology | 1999 | PMID: 10970245 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DES | - | - | - | - |
Text-mined citations for rs62635763 ...
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.