ClinVar Genomic variation as it relates to human health
NM_016011.5(MECR):c.830+2dup
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_016011.5(MECR):c.830+2dup
Variation ID: 449055 Accession: VCV000449055.11
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 1p35.3 1: 29200513-29200514 (GRCh38) [ NCBI UCSC ] 1: 29527026 (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 23, 2017 Feb 14, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016011.5:c.830+2dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001024732.4:c.602+2dup splice donor NM_001349711.2:c.602+2dup splice donor NM_001349712.2:c.602+2dup splice donor NM_001349713.2:c.602+2dup splice donor NM_001349714.2:c.602+2dup splice donor NM_001349715.2:c.935+2dup splice donor NM_001349716.2:c.914+2dup splice donor NM_001349717.2:c.680+2dup splice donor NR_146212.2:n.987dup non-coding transcript variant NC_000001.11:g.29200514dup NC_000001.10:g.29527026dup NG_053058.1:g.35445dup - Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:29200513:A:AA
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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.
The Genome Aggregation Database (gnomAD) 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00014
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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MECR | - | - |
GRCh38 GRCh37 |
283 | 297 |
Conditions - Germline
Condition
Help
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
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2024 | RCV000521566.4 | |
Pathogenic (3) |
criteria provided, single submitter
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Jan 16, 2018 | RCV000626033.6 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2016 | RCV000755158.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2023 | RCV003314605.1 |
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
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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
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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Likely pathogenic
(Aug 09, 2017)
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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: SCV000616771.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The c.830+2dupT variant in the MECR gene has been reported in two unrelated families segregating an autosomal recessive form of childhood-onset dystonia with optic atrophy … (more)
The c.830+2dupT variant in the MECR gene has been reported in two unrelated families segregating an autosomal recessive form of childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (Heimer et al., 2016). This variant destroys the canonical splice donor site in intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.830+2dupT variant is not observed at a significant frequency in large population cohorts and is not observed in the homozygous state in any individual within these cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.830+2dupT as a likely pathogenic variant. (less)
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Pathogenic
(Jan 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000746648.1 First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018 |
Comment:
Compound heterozygous variants, c.830+2dupT and c.-39G>C, were detected in this individual. The c.830+2dupT variant disrupts the splice donor consensus and has previously been reported as … (more)
Compound heterozygous variants, c.830+2dupT and c.-39G>C, were detected in this individual. The c.830+2dupT variant disrupts the splice donor consensus and has previously been reported as disease causing [PMID 27817865]. The c.-39G>C variant lies in the 5'UTR and has never been published to our knowledge. It is absent from large control databases. Whole exome and Sanger sequencing showed the mother is heterozygous for the c.830+2dupT variant and the father is heterozygous for the c.-39G>C variant. Whole exome and Sanger sequencing also showed the affected sibling is heterozygous for both variants in MECR. Our data indicate that the two variants in the MECR gene are in trans configuration (compound heterozygous) in this patient and the affected sibling. (less)
Number of individuals with the variant: 2
Clinical Features:
Global developmental delay (present) , Gait ataxia (present) , Focal T2 hyperintense basal ganglia lesion (present) , Delayed gross motor development (present) , Cerebral palsy … (more)
Global developmental delay (present) , Gait ataxia (present) , Focal T2 hyperintense basal ganglia lesion (present) , Delayed gross motor development (present) , Cerebral palsy (present) (less)
Age: 5-6 years
Sex: male
Ethnicity/Population group: White
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
Date variant was reported to submitter: 2018-01-16
Testing laboratory interpretation: Pathogenic
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Pathogenic
(Jan 26, 2024)
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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: SCV002214220.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 7 of the MECR gene. It does not directly change the encoded amino acid sequence of the MECR protein. … (more)
This sequence change falls in intron 7 of the MECR gene. It does not directly change the encoded amino acid sequence of the MECR protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs756421370, gnomAD 0.3%). This variant has been observed in individual(s) with MECR-related conditions (PMID: 27817865, 32445240). It has also been observed to segregate with disease in related individuals. This variant is also known as c.830+2insT, c.830+2_830+3insT, IVS7+2dupT. ClinVar contains an entry for this variant (Variation ID: 449055). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MECR function (PMID: 27817865). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 7 skipping and partial intron inclusion and introduces a new termination codon (PMID: 27817865). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial disease
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004014689.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The MECR c.830+2dup variant occurs in a splice region and results in the duplication of a thymine following the consensus splice donor site. This variant … (more)
The MECR c.830+2dup variant occurs in a splice region and results in the duplication of a thymine following the consensus splice donor site. This variant has been reported in a compound heterozygous state with the c.695G>A (p.Gly232Glu) variant in four individuals with features of primary mitochondrial disease from three families, at least two of whom had Jewish ancestry (PMID: 27817865; PMID: 32445240; PMID: 34052969). Fibroblasts from compound heterozygous individuals showed reduced MECR protein expression and reduced protein lipoylation. Reduced electron transport capacity was also observed in cells from some individuals (PMID: 27817865). The c.830+2dup variant has also been reported in trans with a 5'UTR variant in an additional affected sibling pair (PMID: 31160820). The highest frequency of this allele in the Genome Aggregation Database is 0.003086 in the Ashkenazi Jewish population (version 2.1.1). This frequency is consistent with the increased prevalence of MECR-related primary mitochondrial disease among individuals with Ashkenazi Jewish ancestry (PMID: 31070877). cDNA studies using RNA from patient cells have demonstrated that the c.830+2dup variant disrupts splicing, producing two mutant transcripts: one in which exon 7 is skipped and one with partial retention of intron 8 that results in the addition of 108 bp to the mRNA sequence (PMID: 27817865). These missplicing events would be expected to disrupt the catalytic domain and part of the cofactor binding domain. This variant was identified in a compound heterozygous state with the c.695G>A (p.Gly232Glu) variant and segregated with disease. Based on the available evidence, the c.830+2dup variant is classified as likely pathogenic for primary mitochondrial disease. (less)
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Likely pathogenic
(Dec 01, 2016)
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no assertion criteria provided
Method: research
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Childhood Onset Dystonias
Optic atrophy
Affected status: yes
Allele origin:
unknown
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000882980.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Number of individuals with the variant: 3
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Pathogenic
(Jan 08, 2024)
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no assertion criteria provided
Method: literature only
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DYSTONIA, CHILDHOOD-ONSET, WITH OPTIC ATROPHY AND BASAL GANGLIA ABNORMALITIES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000493966.3
First in ClinVar: Jan 23, 2017 Last updated: Jan 26, 2024 |
Comment on evidence:
For discussion of the a 1-bp insertion in the MECR gene (c.830+2_830+3insT, NM_016011.3) that was found in compound heterozygous state in 3 patients from 2 … (more)
For discussion of the a 1-bp insertion in the MECR gene (c.830+2_830+3insT, NM_016011.3) that was found in compound heterozygous state in 3 patients from 2 unrelated families with childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG; 617282) by Heimer et al. (2016), see 608205.0001. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities
Affected status: unknown
Allele origin:
maternal
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GenomeConnect, ClinGen
Accession: SCV000986727.2
First in ClinVar: Aug 30, 2019 Last updated: Sep 29, 2019 |
Comment:
Variant interpretted as Pathogenic and reported most recently on 01-16-2018 by Lab or GTR ID 505801. GenomeConnect assertions are reported exactly as they appear on … (more)
Variant interpretted as Pathogenic and reported most recently on 01-16-2018 by Lab or GTR ID 505801. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the optic nerve (present) , Abnormality of coordination (present) , Hypertonia (present) , Generalized hypotonia (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
Date variant was reported to submitter: 2018-01-16
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the optic nerve (present) , Ptosis (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) … (more)
Abnormality of the optic nerve (present) , Ptosis (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Autistic behavior (present) , Short attention span (present) , Abnormality of the male genitalia (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
Date variant was reported to submitter: 2018-01-16
Testing laboratory interpretation: Pathogenic
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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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Genetic and Clinical Predictors of Ataxia in Pediatric Primary Mitochondrial Disorders. | Martin-Saavedra JS | Cerebellum (London, England) | 2022 | PMID: 34052969 |
Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations. | Alves CAPF | Annals of neurology | 2020 | PMID: 32445240 |
Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts. | Frésard L | Nature medicine | 2019 | PMID: 31160820 |
MECR-Related Neurologic Disorder. | Adam MP | - | 2019 | PMID: 31070877 |
MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder. | Heimer G | American journal of human genetics | 2016 | PMID: 27817865 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs756421370 ...
HelpRecord last updated Feb 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.