ClinVar Genomic variation as it relates to human health
NM_001195518.2(MICU1):c.735+1G>A
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_001195518.2(MICU1):c.735+1G>A
Variation ID: 101046 Accession: VCV000101046.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q22.1 10: 72477173 (GRCh38) [ NCBI UCSC ] 10: 74236931 (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 13, 2014 Feb 14, 2024 Oct 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001195518.2:c.735+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001195519.2:c.141+1G>A splice donor NM_001363513.2:c.753+1G>A splice donor NM_006077.4:c.741+1G>A splice donor NC_000010.11:g.72477173C>T NC_000010.10:g.74236931C>T NG_033179.1:g.154019G>A - Protein change
- Other names
- IVS7DS, G-A, +1
- Canonical SPDI
- NC_000010.11:72477172: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00010
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
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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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MICU1 | - | - |
GRCh38 GRCh37 |
293 | 309 |
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
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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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 8, 2022 | RCV000087304.10 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Oct 5, 2023 | RCV001573399.7 |
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
(May 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Proximal myopathy with extrapyramidal signs
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV002577369.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
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Likely pathogenic
(Jun 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Proximal myopathy with extrapyramidal signs
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001653101.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Comment:
The c.741+1G>A variant in MICU1 has been reported in the homozygous state in 2 sibling pairs with proximal myopathy with extrapyramidal signs from unrelated Dutch … (more)
The c.741+1G>A variant in MICU1 has been reported in the homozygous state in 2 sibling pairs with proximal myopathy with extrapyramidal signs from unrelated Dutch families (Logan 2014 PMID: 24336167). It has also been reported in ClinVar (Variation ID 101046) and has been identified in 0.01% (9/73090) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and in vitro functional studies using patient mRNA have shown that this variant affects splicing and leads to markedly decreased MICU1 mRNA and loss of protein levels (Logan 2014 PMID: 24336167). Loss of function variants, including splice variants, have been reported in individuals with proximal myopathy with extrapyramidal signs. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive proximal myopathy with extrapyramidal signs. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PP1. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Proximal myopathy with extrapyramidal signs
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579103.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4_MOD, PM2_SUP, PM3_SUP
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(May 24, 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: SCV003927512.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24336167, 33386810) (less)
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Pathogenic
(Oct 05, 2023)
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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: SCV003441630.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 8 of the MICU1 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 8 of the MICU1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs369915689, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with clinical features of myopathy with extrapyramidal signs (PMID: 24336167). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 101046). Studies have shown that disruption of this splice site results in retention of 155 bp of intron 8 and introduces a premature termination codon (PMID: 24336167). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2014)
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no assertion criteria provided
Method: literature only
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MYOPATHY WITH EXTRAPYRAMIDAL SIGNS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000120182.2
First in ClinVar: Mar 13, 2014 Last updated: Jun 08, 2020 |
Comment on evidence:
In 4 children from 2 unrelated Dutch families with myopathy with extrapyramidal signs (MPXPS; 615673), Logan et al. (2014) identified a homozygous G-to-A transition in … (more)
In 4 children from 2 unrelated Dutch families with myopathy with extrapyramidal signs (MPXPS; 615673), Logan et al. (2014) identified a homozygous G-to-A transition in intron 7 of the MICU1 gene (c.741+1G-A), resulting in a frameshift and premature termination. The mutation was found by whole-exome sequencing. The mutation was shown to undergo nonsense-mediated mRNA decay, resulting in a loss of protein. Haplotype analysis suggested a founder effect. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799217.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808842.1 First in ClinVar: Aug 26, 2021 Last updated: Aug 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927979.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001975326.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. | Logan CV | Nature genetics | 2014 | PMID: 24336167 |
Text-mined citations for rs369915689 ...
HelpRecord last updated May 08, 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.