ClinVar Genomic variation as it relates to human health
NM_014251.3(SLC25A13):c.615+5G>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_014251.3(SLC25A13):c.615+5G>A
Variation ID: 21517 Accession: VCV000021517.51
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q21.3 7: 96193032 (GRCh38) [ NCBI UCSC ] 7: 95822344 (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 Jun 17, 2024 Mar 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014251.3:c.615+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001160210.2:c.615+5G>A intron variant NC_000007.14:g.96193032C>T NC_000007.13:g.95822344C>T NG_012247.2:g.134116G>A - Protein change
- Other names
- IVS6+5G>A
- Canonical SPDI
- NC_000007.14:96193031: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00011
Exome Aggregation Consortium (ExAC) 0.00015
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00003
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
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. |
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SLC25A13 | - | - |
GRCh38 GRCh37 |
833 | 879 |
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. |
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Pathogenic (2) |
criteria provided, single submitter
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Jun 30, 2022 | RCV000020707.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV000811639.7 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2022 | RCV000733522.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 9, 2022 | RCV000779548.6 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV001272104.2 | |
Pathogenic (2) |
criteria provided, single submitter
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Mar 21, 2024 | RCV002259308.4 | |
SLC25A13-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Nov 9, 2023 | RCV003924850.1 |
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
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 31, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000861599.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(May 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Citrullinemia type II
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002548481.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: SLC25A13 c.615+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: SLC25A13 c.615+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions demonstrating that this variant affects mRNA splicing (Zhang_2014). The variant allele was found at a frequency of 0.00011 in 251214 control chromosomes (gnomAD). c.615+5G>A has been reported in the literature in multiple individuals affected with citrin deficiency (e.g. Song_2011, Zhang_2014, Lin_2019). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Sep 01, 2022)
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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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Revvity Omics, Revvity
Accession: SCV002022602.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Citrin deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000951915.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 6 of the SLC25A13 gene. It does not directly change the encoded amino acid sequence of the SLC25A13 protein. … (more)
This sequence change falls in intron 6 of the SLC25A13 gene. It does not directly change the encoded amino acid sequence of the SLC25A13 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80338717, gnomAD 0.1%). This variant has been observed in individual(s) with citrin deficiency (PMID: 19036621, 20301360, 21134364, 21507300, 24586645; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS6+5G>A. ClinVar contains an entry for this variant (Variation ID: 21517). 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 retention of intron 6 and introduces a premature termination codon (PMID: 24586645). 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
(Mar 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Citrullinemia, type II, adult-onset
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004203612.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Oct 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Citrullinemia, type II, adult-onset
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000916217.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The SLC25A13 c.615+5G>A variant is one of the most commonly identified variants in probands of East Asian ethnicity with citrin deficiency. Across a subset of … (more)
The SLC25A13 c.615+5G>A variant is one of the most commonly identified variants in probands of East Asian ethnicity with citrin deficiency. Across a subset of the literature, the c.615+5G>A variant (also reported as IVS6+5G>A) has been detected in a compound heterozygous state in at least 21 probands and in a heterozygous state with no second variant identified in at least 2 probands (Kobayashi et al. 2003; Saheki et al. 2003; Tabata et al. 2008; Dimmock et al. 2009; Lin et al. 2010; Song et al. 2011; Wen et al. 2011; Zhang et al. 2014). The c.615+5G>A variant was reported in 14 of 8500 control subjects and is reported at a frequency of 0.002087 in the East Asian population of the Exome Aggregation Consortium. Zhang et al. (2014) performed functional studies on the variant, confirming that splicing is disrupted which then leads to the inclusion of the intron and ultimately causes a premature truncation of the protein. Based on the collective evidence, the c.615+5G>A variant is classified as pathogenic for citrin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jun 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neonatal intrahepatic cholestasis due to citrin deficiency
Affected status: yes
Allele origin:
germline
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Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam
Additional submitter:
Hepatology Department, National Children’s Hospital
Accession: SCV002546530.2
First in ClinVar: Jan 07, 2023 Last updated: Feb 25, 2023 |
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Pathogenic
(Nov 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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SLC25A13-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004739863.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The SLC25A13 c.615+5G>A variant is predicted to interfere with splicing. This variant is a commonly reported SLC25A13 pathogenic variant in the Chinese population (e.g., Fu … (more)
The SLC25A13 c.615+5G>A variant is predicted to interfere with splicing. This variant is a commonly reported SLC25A13 pathogenic variant in the Chinese population (e.g., Fu et al. 2011. PubMed ID: 20927635; Song et al. 2011. PubMed ID: 21424115). RT-PCR analysis of transcripts from a SLC25A13 allele harboring the c.615+5G>A variant revealed that the entirety of intron 6 was retained in the transcript, confirming a splicing defect (Zhang et al. 2014. PubMed ID: 24586645). Please note that this variant has often been referred to as IVS6+5G>A in the literature. This variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-95822344-C-T). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 07, 2017)
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no assertion criteria provided
Method: curation
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Neonatal intrahepatic cholestasis due to citrin deficiency
Affected status: no
Allele origin:
germline
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SingHealth Duke-NUS Institute of Precision Medicine
Accession: SCV000853102.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Late-onset citrullinemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453751.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Citrullinemia, type II, adult-onset
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000041262.3
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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The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis. | Nguyen MT | Journal of human genetics | 2023 | PMID: 36599957 |
Expanded newborn screening for inherited metabolic disorders and genetic characteristics in a southern Chinese population. | Lin Y | Clinica chimica acta; international journal of clinical chemistry | 2019 | PMID: 30904546 |
Citrin Deficiency. | Adam MP | - | 2017 | PMID: 20301360 |
Clinical, molecular and functional investigation on an infant with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). | Zhang ZH | PloS one | 2014 | PMID: 24586645 |
[SLC25A13 gene analysis in neonates with intrahepatic cholestasis caused by citrin deficiency]. | Wen PQ | Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics | 2011 | PMID: 21507300 |
Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center. | Song YZ | International journal of molecular medicine | 2011 | PMID: 21424115 |
High resolution melting analysis for the detection of SLC25A13 gene mutations in Taiwan. | Lin JT | Clinica chimica acta; international journal of clinical chemistry | 2011 | PMID: 21134364 |
Citrin deficiency, a perplexing global disorder. | Dimmock D | Molecular genetics and metabolism | 2009 | PMID: 19036621 |
Identification of 13 novel mutations including a retrotransposal insertion in SLC25A13 gene and frequency of 30 mutations found in patients with citrin deficiency. | Tabata A | Journal of human genetics | 2008 | PMID: 18392553 |
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 |
Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency. | Lu YB | Journal of human genetics | 2005 | PMID: 16059747 |
Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. | Saheki T | Molecular genetics and metabolism | 2004 | PMID: 15050970 |
Screening of nine SLC25A13 mutations: their frequency in patients with citrin deficiency and high carrier rates in Asian populations. | Kobayashi K | Molecular genetics and metabolism | 2003 | PMID: 14680984 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC25A13 | - | - | - | - |
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Text-mined citations for rs80338717 ...
HelpRecord last updated Jun 23, 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.