ClinVar Miner

Submissions for variant NM_014251.3(SLC25A13):c.615+5G>A (rs80338717)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000733522 SCV000861599 pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2020-10-15 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs80338717, ExAC 0.2%). This variant has been observed in combination with pathogenic variants in several individuals affected with citrin deficiency (PMID: 19036621, 20301360, 21134364, 21507300, 24586645, Invitae). This variant is also known as IVS6+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 21517). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this change results in the skpiping of exon 6 (PMID: 24586645). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000020707 SCV000041262 pathologic Neonatal intrahepatic cholestasis caused by citrin deficiency 2012-01-05 no assertion criteria provided curation Converted during submission to Pathogenic.
SingHealth Duke-NUS Institute of Precision Medicine RCV000020707 SCV000853102 pathogenic Neonatal intrahepatic cholestasis caused by 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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