ClinVar Miner

Submissions for variant NM_014251.3(SLC25A13):c.615+5G>A

gnomAD frequency: 0.00003  dbSNP: rs80338717
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000733522 SCV000861599 pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000779548 SCV000916217 pathogenic Citrullinemia type II 2018-10-04 criteria provided, single submitter clinical testing 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.
Invitae RCV000811639 SCV000951915 pathogenic Citrin deficiency 2024-01-30 criteria provided, single submitter clinical testing 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.
Revvity Omics, Revvity RCV000733522 SCV002022602 likely pathogenic not provided 2022-09-01 criteria provided, single submitter clinical testing
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam RCV000020707 SCV002546530 pathogenic Neonatal intrahepatic cholestasis due to citrin deficiency 2022-06-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779548 SCV002548481 pathogenic Citrullinemia type II 2022-05-09 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV002259308 SCV004203612 pathogenic Citrullinemia, type II, adult-onset 2024-03-21 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003924850 SCV004739863 pathogenic SLC25A13-related disorder 2023-11-09 criteria provided, single submitter clinical testing 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.
GeneReviews RCV002259308 SCV000041262 not provided Citrullinemia, type II, adult-onset no assertion provided literature only
SingHealth Duke-NUS Institute of Precision Medicine RCV000020707 SCV000853102 pathogenic Neonatal intrahepatic cholestasis due to citrin deficiency 2017-06-07 no assertion criteria provided curation
Natera, Inc. RCV001272104 SCV001453751 pathogenic Late-onset citrullinemia 2020-09-16 no assertion criteria provided clinical testing

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