ClinVar Genomic variation as it relates to human health
NM_213595.4(ISCU):c.418+382G>C
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_213595.4(ISCU):c.418+382G>C
Variation ID: 223141 Accession: VCV000223141.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.3 12: 108567650 (GRCh38) [ NCBI UCSC ] 12: 108961426 (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 Mar 5, 2016 Feb 14, 2024 Dec 8, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_213595.4:c.418+382G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001301140.1:c.419-8G>C intron variant NM_001301141.1:c.419-270G>C intron variant NM_001320042.1:c.419-8G>C intron variant NM_014301.4:c.343+382G>C intron variant NC_000012.12:g.108567650G>C NC_000012.11:g.108961426G>C NG_011857.1:g.10133G>C - Protein change
- Other names
- IVS5, G-C, +382
- Canonical SPDI
- NC_000012.12:108567649: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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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ISCU | - | - |
GRCh38 GRCh37 |
145 | 174 |
Conditions - Germline
Condition
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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
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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 (3) |
criteria provided, single submitter
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Apr 7, 2021 | RCV000208760.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2021 | RCV002517413.2 |
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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Pathogenic
(Apr 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary myopathy with lactic acidosis due to ISCU deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001554465.1
First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Family history: no
Secondary finding: no
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Pathogenic
(Dec 08, 2021)
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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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Invitae
Accession: SCV003441167.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This variant has been observed in individuals with hereditary myopathy with lactic acidosis (PMID: 18296749, 18304497, 20206689). It has also been observed to segregate with … (more)
This variant has been observed in individuals with hereditary myopathy with lactic acidosis (PMID: 18296749, 18304497, 20206689). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs767000507, gnomAD 0.006%). This sequence change falls in intron 4 of the ISCU gene. It does not directly change the encoded amino acid sequence of the ISCU protein. ClinVar contains an entry for this variant (Variation ID: 223141). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects ISCU function (PMID: 18304497, 19846308, 30209894). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. (less)
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Pathogenic
(Mar 01, 2012)
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no assertion criteria provided
Method: literature only
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MYOPATHY WITH LACTIC ACIDOSIS, HEREDITARY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020968.4
First in ClinVar: Apr 04, 2013 Last updated: Feb 08, 2018 |
Comment on evidence:
In 3 patients with myopathy with exercise intolerance (HML; 255125) from northern Sweden, Mochel et al. (2008) found homozygosity for an intronic G-to-C transversion (7044G-C, … (more)
In 3 patients with myopathy with exercise intolerance (HML; 255125) from northern Sweden, Mochel et al. (2008) found homozygosity for an intronic G-to-C transversion (7044G-C, or IVS5+382G-C) in the ISCU gene. There were 3 heterozygous carriers of the mutation among 568 Swedish chromosomes, resulting in a frequency of approximately 1 in 188 in this population. Western blot analysis of patient muscle showed a substantial reduction of the normal mitochondrial isoform (ISCU2) compared to controls. The mutation was thought to strengthen a weak splicing acceptor site, with consequent retention of a 100-bp intronic sequence upstream of the known terminal exon, introduction of a stop codon, and decreased levels of ISCU mRNA and protein. The depletion of mitochondrial ISCU in muscle would account for the biochemical and clinical phenotype, which is characterized by a deficiency in mitochondrial iron-sulfur proteins and impaired muscle oxidative metabolism. Independently, Olsson et al. (2008) identified homozygosity the G-to-C transversion in intron 5 of the ISCU gene in 15 affected members from 9 families with hereditary myopathy and lactic acidosis. RT-PCR studies showed aberrant splicing of the ISCU mRNA in patient muscle biopsies compared to controls, with significantly decreased levels of the mitochondrial ISCU2 isoform. However, patient mRNA did not correspond to the cytosolic ISCU1 isoform; rather, patient mRNA contained a 100-bp sequence from intron 5, inserted between exons 4 and 5. This was due to activation of cryptic acceptor and donor splice sites. The added intron sequence resulted in an alternative C-terminal 15 amino acids followed by a stop codon. Kollberg and Holme (2009) demonstrated that an antisense oligonucleotide specifically targeting activated cryptic splice sites in the ISCU gene induced by the 7044G-C mutation was able to restore the correct reading frame in cultured fibroblasts derived from patients with homozygous mutation. The restoration in cells was stable, with correctly spliced mRNA remaining the dominant RNA species after 21 days. Sanaker et al. (2010) reported a Norwegian woman with the disorder who was homozygous for the 7044G-C mutation. Activities of mitochondrial complexes I, II, and III were decreased in skeletal muscle samples, whereas cultured myoblasts and fibroblasts had nearly normal activity. Western blot analysis showed decreased ISCU type I in muscle, myoblasts, and fibroblasts. The steady-state level of ISCU mRNA was significantly decreased in patient myoblasts (20% of controls), moderately decreased in muscle (54% of controls), and normal in fibroblasts. The mutant transcript containing exons 5, 5A, and 6 was the predominant (90%) species in patient muscle, although low levels (10%) of the normal transcript with exons 5 and 6 were also found. Control samples had low levels of the mutant transcript as well, suggesting that the mutation strengthens a preexisting weak splice site. Patient blood, myoblasts, and fibroblasts had equal amounts of both transcripts. Patient muscle also specifically showed an increase in mitochondrial content compared to controls, perhaps representing a compensatory mechanism. These findings suggested that the ratio between normally spliced and abnormally spliced transcript is important in determining tissue specificity of the defect. Nordin et al. (2011) demonstrated tissue-specific expression of the mutant spliced ISCU protein. RT-PCR analysis of postmortem tissue samples from a patient with the IVS5 mutation showed that the muscle had the highest relative amount of mutant mRNA (80%), with the transcript containing the 100-bp insert being the most common. In heart and liver, the wildtype mRNA predominated, representing 70% total mRNA in heart and 54% in liver. The findings were confirmed by Western blot analysis of the tissues. The results indicated that tissue-specific differential splicing underlies the muscle-specific phenotype in patients with this ISCU mutation. Nordin et al. (2012) found that the RNA-binding factor IGF2BP1 (608288) had a higher affinity for mutant ISCU than wildtype ISCU. PTBP1 (600693), implicated in repression of incorrect splicing, bound strongly to both wildtype and mutant ISCU. In vitro studies using an ISCU minigene showed that PTBP1 dramatically repressed incorrect splicing when coexpressed with the mutant minigene, resulting in a 0.13-fold change of the mutant:normal transcript ratio. In contrast, IGF2B1 and RBM39 (604739) resulted in an increased mutant:normal transcript ratio and were able to counteract the effect of PTBP1. Nordin et al. (2012) suggested that IGF2BP1 in particular may be a factor that promotes the inclusion of the pseudoexon in mutant ISCU by interfering with PTBP1 binding and repression of mutant ISCU. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Hereditary myopathy with lactic acidosis due to ISCU deficiency
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000264645.2
First in ClinVar: Mar 05, 2016 Last updated: Oct 01, 2022 |
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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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PTBP1 acts as a dominant repressor of the aberrant tissue-specific splicing of ISCU in hereditary myopathy with lactic acidosis. | Rawcliffe DFR | Molecular genetics & genomic medicine | 2018 | PMID: 30209894 |
Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2016 | PMID: 20301757 |
The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be derepressed by IGF2BP1. | Nordin A | Human mutation | 2012 | PMID: 22125086 |
Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice. | Nordin A | Human genetics | 2011 | PMID: 21165651 |
Differences in RNA processing underlie the tissue specific phenotype of ISCU myopathy. | Sanaker PS | Biochimica et biophysica acta | 2010 | PMID: 20206689 |
Antisense oligonucleotide therapeutics for iron-sulphur cluster deficiency myopathy. | Kollberg G | Neuromuscular disorders : NMD | 2009 | PMID: 19846308 |
Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. | Mochel F | American journal of human genetics | 2008 | PMID: 18304497 |
Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect. | Olsson A | Human molecular genetics | 2008 | PMID: 18296749 |
Text-mined citations for rs767000507 ...
HelpRecord last updated Feb 14, 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.