Nonsense variant predicted to result in protein truncation or nonsense mediated decay 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: 29288388, 31130284, 28454995, 30264509, 33428302, 30919572, 29721912)
ClinVar Genomic variation as it relates to human health
NM_001195518.2(MICU1):c.547C>T (p.Gln183Ter)
Germline
Classification
Help
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.
(8)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(5); Uncertain significance(1)
Pathogenic(5); Uncertain significance(1)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001195518.2(MICU1):c.547C>T (p.Gln183Ter)
Variation ID: 265243 Accession: VCV000265243.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q22.1 10: 72508260 (GRCh38) [ NCBI UCSC ] 10: 74268018 (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 Dec 19, 2017 Jul 15, 2024 Apr 26, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001195518.2:c.547C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001182447.1:p.Gln183Ter nonsense NM_001195519.2:c.58+15542C>T intron variant NM_001363513.2:c.565C>T NP_001350442.1:p.Gln189Ter nonsense NM_006077.4:c.553C>T NP_006068.2:p.Gln185Ter nonsense NC_000010.11:g.72508260G>A NC_000010.10:g.74268018G>A NG_033179.1:g.122932C>T - Protein change
- Q185*, Q183*, Q189*
- Other names
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MICU1, GLN185TER (rs755651388)
- Canonical SPDI
- NC_000010.11:72508259: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.
- -
-
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
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| MICU1 | - | - |
GRCh38 GRCh37 |
297 | 313 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 9, 2024 | RCV000254969.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001814130.1 | |
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Apr 26, 2024 | RCV000985189.8 |
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 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321891.10
First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay 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: 29288388, 31130284, 28454995, 30264509, 33428302, 30919572, 29721912) (less)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Proximal myopathy with extrapyramidal signs
Affected status: yes
Allele origin:
germline
|
Pathology and Clinical Laboratory Medicine, King Fahad Medical City
Accession: SCV001438874.1
First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020 |
Number of individuals with the variant: 3
Ethnicity/Population group: Arab
Geographic origin: Middle East
|
|
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Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755137.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
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Pathogenic
(Jan 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003441631.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln185*) in the MICU1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln185*) in the MICU1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MICU1 are known to be pathogenic (PMID: 24336167). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with MICU1-related conditions (PMID: 29721912). ClinVar contains an entry for this variant (Variation ID: 265243). For these reasons, this variant has been classified as Pathogenic. (less)
|
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Uncertain significance
(Feb 11, 2024)
|
criteria provided, single submitter
Method: research
|
Proximal myopathy with extrapyramidal signs
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004800993.2
First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024 |
|
|
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Pathogenic
(Apr 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Proximal myopathy with extrapyramidal signs
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005076408.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
Variant summary: CBARA1 c.553C>T (p.Gln185X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: CBARA1 c.553C>T (p.Gln185X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 204610 control chromosomes. c.553C>T has been reported in the literature in multiple individuals affected with MICU1 related conditions (Musa_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29721912). ClinVar contains an entry for this variant (Variation ID: 265243). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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|
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Likely pathogenic
(Sep 26, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Proximal myopathy with extrapyramidal signs
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133207.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
|
|
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Pathogenic
(Jun 24, 2021)
|
no assertion criteria provided
Method: literature only
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MYOPATHY WITH EXTRAPYRAMIDAL SIGNS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001335231.1
First in ClinVar: Jun 08, 2020 Last updated: Jun 08, 2020 |
Comment on evidence:
In 13 children with myopathy with extrapyramidal signs (MPXPS; 615673) from 10 Arab families, 8 of which were consanguineous, from Qatar, Saudi Arabia, and Kuwait, … (more)
In 13 children with myopathy with extrapyramidal signs (MPXPS; 615673) from 10 Arab families, 8 of which were consanguineous, from Qatar, Saudi Arabia, and Kuwait, Musa et al. (2019) identified a c.553C-T transition in the MICU1 gene, resulting in a gln185-to-ter (Q185X) substitution. In 12 patients the mutation was present in homozygous state and in 1 patient (family 7) it was present in compound heterozygous state with an intragenic duplication of exons 9 and 10 (605084.0004). The mutations were identified by whole-exome or targeted sequencing and confirmed by capillary sequencing or CGH array. The Q185X substitution occurs in the N-terminal domain before the calcium-binding EF hand domains but after the mitochondrial targeting signal, predicting a loss of function. Musa et al. (2019) noted that the Q185X variant has a minor allele frequency (MAF) of 1:60,000 in the ExAC database. Among 5,016 healthy Middle Eastern individuals, they found that 9 carried the Q185X variant (MAF = 0.0009), indicating a carrier rate for this founder mutation as high as 1:557 (0.2%) in this population. In a girl (patient 1), born to consanguineous Turkish parents, with MPXPS, Kohlschmidt et al. (2021) identified homozygosity for the Middle Eastern Q185X founder mutation in the MICU1 gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient lymphoblastic cells demonstrated absent protein expression and dysregulation of mitochondrial calcium uptake. (less)
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Gln185*) in the MICU1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MICU1 are known to be pathogenic (PMID: 24336167). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with MICU1-related conditions (PMID: 29721912). ClinVar contains an entry for this variant (Variation ID: 265243). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: CBARA1 c.553C>T (p.Gln185X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 204610 control chromosomes. c.553C>T has been reported in the literature in multiple individuals affected with MICU1 related conditions (Musa_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29721912). ClinVar contains an entry for this variant (Variation ID: 265243). Based on the evidence outlined above, the variant was classified as pathogenic.
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. |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay 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: 29288388, 31130284, 28454995, 30264509, 33428302, 30919572, 29721912)
Comment:
This sequence change creates a premature translational stop signal (p.Gln185*) in the MICU1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MICU1 are known to be pathogenic (PMID: 24336167). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with MICU1-related conditions (PMID: 29721912). ClinVar contains an entry for this variant (Variation ID: 265243). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: CBARA1 c.553C>T (p.Gln185X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 204610 control chromosomes. c.553C>T has been reported in the literature in multiple individuals affected with MICU1 related conditions (Musa_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29721912). ClinVar contains an entry for this variant (Variation ID: 265243). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular pathophysiology of human MICU1 deficiency. | Kohlschmidt N | Neuropathology and applied neurobiology | 2021 | PMID: 33428302 |
| A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients. | Musa S | JIMD reports | 2019 | PMID: 29721912 |
| 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 rs777327250 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.