ClinVar Genomic variation as it relates to human health
NM_012210.4(TRIM32):c.1459G>A (p.Asp487Asn)
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_012210.4(TRIM32):c.1459G>A (p.Asp487Asn)
Variation ID: 7350 Accession: VCV000007350.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q33.1 9: 116699201 (GRCh38) [ NCBI UCSC ] 9: 119461480 (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 13, 2017 Feb 14, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001365068.1:c.2806+26570C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_012210.4:c.1459G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036342.2:p.Asp487Asn missense NM_001099679.2:c.1459G>A NP_001093149.1:p.Asp487Asn missense NM_001365069.1:c.2794+26570C>T intron variant NM_001379048.1:c.1459G>A NP_001365977.1:p.Asp487Asn missense NM_001379049.1:c.1459G>A NP_001365978.1:p.Asp487Asn missense NM_001379050.1:c.1459G>A NP_001365979.1:p.Asp487Asn missense NM_014010.5:c.2653+26570C>T intron variant NC_000009.12:g.116699201G>A NC_000009.11:g.119461480G>A NG_011619.1:g.16900G>A NG_021409.2:g.720857C>T LRG_211:g.16900G>A LRG_211t1:c.1459G>A LRG_211p1:p.Asp487Asn Q13049:p.Asp487Asn - Protein change
- D487N
- Other names
- TRIM32, ASP487ASN (rs111033570)
- Canonical SPDI
- NC_000009.12:116699200:G: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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
Help
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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ASTN2 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
141 | 908 | |
TRIM32 | - | - |
GRCh38 GRCh37 |
- | 747 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jul 10, 2023 | RCV000007775.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 8, 2015 | RCV000414917.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000538874.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2016 | RCV001198489.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2019 | RCV001781203.4 |
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
Help
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 03, 2018)
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criteria provided, single submitter
Method: research
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Sarcotubular myopathy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164476.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The homozygous p.Asp487Asn variant in TRIM32 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in … (more)
The homozygous p.Asp487Asn variant in TRIM32 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.001791% (2/111664) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033570). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Asp487Asn variant in TRIM32 has been reported in 55 Hutterite individuals with LGMD and segregated with disease in 8 affected relatives from 3 families (PMID: 11822024, 15786463). Animal models in mice have shown that this variant causes Limb-Girdle Muscular Dystrophy by lowering protein stability but not mRNA levels. Knock-in mice with this variant showed a similar neuromuscular phenotype to trim32 knock-out mice, supporting pathogenicity as a loss of function variant (PMID: 21775502). This variant has also been reported pathogenic in ClinVar by multiple submitters (Variation ID: 7350). In summary, the p.Asp487Asn variant is pathogenic. ACMG/AMP Criteria applied: PM2, PP1_Strong, PS3 (Richards 2015). (less)
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Pathogenic
(Jul 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Sarcotubular myopathy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045874.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Elevated circulating creatine kinase concentration (present) , Coronary artery stenosis (present) , Hypercholesterolemia (present)
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Pathogenic
(Feb 22, 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: SCV002022423.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Bardet-Biedl syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000636501.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 487 of the TRIM32 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 487 of the TRIM32 protein (p.Asp487Asn). This variant is present in population databases (rs111033570, gnomAD 0.002%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy type 2H and sarcotubular myopathy (PMID: 11822024, 15786463, 23142638). It is commonly reported in individuals of Hutterite ancestry (PMID: 11822024, 15786463, 23142638). ClinVar contains an entry for this variant (Variation ID: 7350). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TRIM32 function (PMID: 21775502). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 08, 2015)
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criteria provided, single submitter
Method: clinical testing
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Myopathy
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492867.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Bardet-Biedl syndrome 11
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369440.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. This variant was detected in homozygous state.
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Pathogenic
(Oct 05, 2012)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 8
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027976.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 28, 2018 |
Comment on evidence:
Frosk et al. (2002) found homozygosity for an asp487-to-asn (D487N) missense mutation in the TRIM32 gene as a causative mutation in the mild autosomal recessive … (more)
Frosk et al. (2002) found homozygosity for an asp487-to-asn (D487N) missense mutation in the TRIM32 gene as a causative mutation in the mild autosomal recessive myopathy observed in Manitoba Hutterites (LGMDR8; 254110). Frosk et al. (2002) stated that of 60 cases of LGMD studied in Manitoba Hutterites, most were caused by the D487N mutation. Schoser et al. (2005) identified the homozygous D487N mutation in the patients reported by Jerusalem et al. (1973) and Muller-Felber et al. (1999), confirming that they had LGMDR8. In addition, haplotype analysis showed that all LGMDR8 patients shared the same haplotype, suggesting that the mutation arose before the emergence of the Hutterite religion in central Europe in the 16th century. Schoser et al. (2005) noted the phenotypic variability caused by the same mutation. Frosk et al. (2005) reported a Hutterite family in which 2 boys, aged 7 and 10 years, were homozygous for both the D487N mutation and an LGMD2I (LGMDR9; 607155)-related FKRP mutation (L276I; 606596.0004). Although they presented at an early age with exercise intolerance and increased serum creatine kinase, the clinical phenotype was not significantly more severe than that of patients with isolated LGMD2H or LGMD2I. Both parents and 3 other sibs were homozygous for the D487N mutation, with highly variable phenotypic expression. In vitro functional expression studies by Saccone et al. (2008) demonstrated that D487N-mutant protein lost the ability to homodimerize and showed inhibited binding to full-length UBE2N (603679). The consequences of this mutation were similar to complete deletion of the coiled coil-NHL domains, suggesting a dramatic effect on protein folding. Locke et al. (2009) showed that D487N-mutant protein impaired TRIM32 ubiquitin ligase activity towards dysbindin (DTNBP1; 607145) and mislocalized in heterologous cells. The D487N mutant could bind to both dysbindin and its ubiquitin-conjugating E2 enzyme but was defective in monoubiquitination. Locke et al. (2009) suggest that D487N mutation may impair substrate ubiquitination. Among 1,493 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 228 heterozygotes and 9 homozygotes for the D487N mutation in the TRIM32 gene, for a frequency of 0.153, or 1 in 6.5. The carrier frequency in other populations was unknown, with only 2 non-Hutterite cases having been reported (Schoser et al., 2005). The 9 homozygous individuals ranged in age from 10 to 42 years, and were unaware of their status. (less)
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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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Scapuloperoneal muscular dystrophy phenotype due to TRIM32-sarcotubular myopathy in South Dakota Hutterite. | Liewluck T | Neuromuscular disorders : NMD | 2013 | PMID: 23142638 |
A population-based study of autosomal-recessive disease-causing mutations in a founder population. | Chong JX | American journal of human genetics | 2012 | PMID: 22981120 |
The common missense mutation D489N in TRIM32 causing limb girdle muscular dystrophy 2H leads to loss of the mutated protein in knock-in mice resulting in a Trim32-null phenotype. | Kudryashova E | Human molecular genetics | 2011 | PMID: 21775502 |
TRIM32 is an E3 ubiquitin ligase for dysbindin. | Locke M | Human molecular genetics | 2009 | PMID: 19349376 |
Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H. | Saccone V | Human mutation | 2008 | PMID: 17994549 |
Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I. | Frosk P | European journal of human genetics : EJHG | 2005 | PMID: 15886712 |
Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H. | Schoser BG | Annals of neurology | 2005 | PMID: 15786463 |
Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. | Frosk P | American journal of human genetics | 2002 | PMID: 11822024 |
Phenotypic variability in two brothers with sarcotubular myopathy. | Müller-Felber W | Journal of neurology | 1999 | PMID: 10399877 |
Sarcotubular myopathy. A newly recognized, benign, congenital, familial muscle disease. | Jerusalem F | Neurology | 1973 | PMID: 4269389 |
Text-mined citations for rs111033570 ...
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.