ClinVar Genomic variation as it relates to human health
NM_014252.4(SLC25A15):c.79G>A (p.Gly27Arg)
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_014252.4(SLC25A15):c.79G>A (p.Gly27Arg)
Variation ID: 5995 Accession: VCV000005995.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.11 13: 40799080 (GRCh38) [ NCBI UCSC ] 13: 41373216 (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 28, 2024 Dec 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014252.4:c.79G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055067.1:p.Gly27Arg missense NR_038258.1:n.2267C>T non-coding transcript variant NR_038259.1:n.2096C>T non-coding transcript variant NC_000013.11:g.40799080G>A NC_000013.10:g.41373216G>A NG_012248.1:g.14670G>A Q9Y619:p.Gly27Arg - Protein change
- G27R
- Other names
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- Canonical SPDI
- NC_000013.11:40799079: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.
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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
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
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
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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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SLC25A15 | - | - |
GRCh38 GRCh37 |
435 | 495 |
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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Dec 24, 2023 | RCV000006361.11 |
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
(Sep 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201675.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000631856.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 27 of the SLC25A15 protein (p.Gly27Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 27 of the SLC25A15 protein (p.Gly27Arg). This variant is present in population databases (rs104894430, gnomAD 0.004%). This missense change has been observed in individuals with hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (PMID: 11552031, 16376511, 25874378). ClinVar contains an entry for this variant (Variation ID: 5995). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC25A15 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC25A15 function (PMID: 12807890, 25818551). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821383.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: SLC25A15 c.79G>A (p.Gly27Arg) results in a non-conservative amino acid change located in the Mitochondrial carrier superfamily domain (IPR023395) of the encoded protein sequence. … (more)
Variant summary: SLC25A15 c.79G>A (p.Gly27Arg) results in a non-conservative amino acid change located in the Mitochondrial carrier superfamily domain (IPR023395) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251488 control chromosomes. c.79G>A has been reported in the literature in multiple individuals affected with Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (example, Salvi_2001, Martinelli_2015, Oliveri_2019). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Fiermonte_2003, Marobbio_2015). The most pronounced variant effect results in complete inability to transport ornithine and citrulline. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 11, 2001)
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no assertion criteria provided
Method: literature only
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HHH SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026543.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a 17-year-old girl with HHH syndrome (238970) since infancy, Salvi et al. (2001) identified a homozygous mutation in the SLC25A15 gene, resulting in a … (more)
In a 17-year-old girl with HHH syndrome (238970) since infancy, Salvi et al. (2001) identified a homozygous mutation in the SLC25A15 gene, resulting in a gly27-to-arg (G27R) substitution. The girl was not mentally retarded and did not have spastic paraparesis, but did show pyramidal signs on neurologic examination. (less)
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Pathogenic
(Feb 23, 2021)
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no assertion criteria provided
Method: clinical testing
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Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002086766.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Corticospinal tract damage in HHH syndrome: a metabolic cause of hereditary spastic paraplegia. | Olivieri G | Orphanet journal of rare diseases | 2019 | PMID: 31443672 |
The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. | Martinelli D | Orphanet journal of rare diseases | 2015 | PMID: 25874378 |
Pathogenic potential of SLC25A15 mutations assessed by transport assays and complementation of Saccharomyces cerevisiae ORT1 null mutant. | Marobbio CM | Molecular genetics and metabolism | 2015 | PMID: 25818551 |
Insights into the mutation-induced HHH syndrome from modeling human mitochondrial ornithine transporter-1. | Wang JF | PloS one | 2012 | PMID: 22292090 |
A novel R275X mutation of the SLC25A15 gene in a Japanese patient with the HHH syndrome. | Torisu H | Brain & development | 2006 | PMID: 16376511 |
The mitochondrial ornithine transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. | Fiermonte G | The Journal of biological chemistry | 2003 | PMID: 12807890 |
Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. | Salvi S | Neurology | 2001 | PMID: 11552031 |
Text-mined citations for rs104894430 ...
HelpRecord last updated Mar 05, 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.