ClinVar Genomic variation as it relates to human health
NM_003850.3(SUCLA2):c.534+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_003850.3(SUCLA2):c.534+1G>A
Variation ID: 5976 Accession: VCV000005976.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.2 13: 47988540 (GRCh38) [ NCBI UCSC ] 13: 48562675 (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 Apr 4, 2013 Feb 14, 2024 Nov 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003850.3:c.534+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000013.11:g.47988540C>T NC_000013.10:g.48562675C>T NG_008241.1:g.17788G>A NG_008241.2:g.17733G>A - Protein change
- Other names
- IVS4DS, G-A, +1
- Canonical SPDI
- NC_000013.11:47988539: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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
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
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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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SUCLA2 | - | - |
GRCh38 GRCh37 |
363 | 453 |
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Nov 13, 2023 | RCV000020560.7 |
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
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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
(Jul 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004029832.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: SUCLA2 c.534+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: SUCLA2 c.534+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, demonstrating that the variant creates multiple abberrant transcripts that are missing exons 2, 3 and some or all of exon 4 (e.g., Carrozzo_2007) The variant allele was found at a frequency of 1.2e-05 in 251194 control chromosomes. c.534+1G>A has been reported in the literature in multiple homozygous individuals affected with Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form With Methylmalonic Aciduria (e.g., Carrozzo_2007) . These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 17301081). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003517009.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 4 of the SUCLA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 4 of the SUCLA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SUCLA2 are known to be pathogenic (PMID: 15877282, 17301081). This variant is present in population databases (rs113994161, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with clinical features of mitochondrial DNA depletion syndrome (PMID: 17301081). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5976). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 17301081). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2007)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL DNA DEPLETION SYNDROME 5 (ENCEPHALOMYOPATHIC TYPE WITH METHYLMALONIC ACIDURIA)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026524.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a total of 16 patients from the Faroe Islands with encephalomyopathic mtDNA depletion syndrome and mild methylmalonic aciduria (612073), Ostergaard et al. (2007) and … (more)
In a total of 16 patients from the Faroe Islands with encephalomyopathic mtDNA depletion syndrome and mild methylmalonic aciduria (612073), Ostergaard et al. (2007) and Carrozzo et al. (2007) independently identified a homozygous G-to-A transition in intron 4 of the SUCLA2 gene, resulting in the skipping of exon 4 and a truncated protein. Carrozzo et al. (2007) referred to the mutation as 534+1G-A. Haplotype analysis indicated a founder effect. The carrier and disease frequencies in this population were estimated to be 2% and 1 in 2,500, respectively. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000041036.2
First in ClinVar: Apr 04, 2013 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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SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria. | Adam MP | - | 2023 | PMID: 20301762 |
SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. | Carrozzo R | Brain : a journal of neurology | 2007 | PMID: 17301081 |
Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. | Ostergaard E | Brain : a journal of neurology | 2007 | PMID: 17287286 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. | Elpeleg O | American journal of human genetics | 2005 | PMID: 15877282 |
Text-mined citations for rs113994161 ...
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.