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

gnomAD frequency: 0.00003  dbSNP: rs80338717

Total submissions: 13

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811639	SCV000951915	pathogenic	Citrin deficiency	2024-03-12	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
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795933	SCV005416845	pathogenic	Neonatal intrahepatic cholestasis due to citrin deficiency; Citrullinemia, type II, adult-onset		criteria provided, single submitter	clinical testing	PS3+PM3_VeryStrong+PP4+PM2_Supporting
Fulgent Genetics, Fulgent Genetics	RCV004795933	SCV005671941	pathogenic	Neonatal intrahepatic cholestasis due to citrin deficiency; Citrullinemia, type II, adult-onset	2024-03-11	criteria provided, single submitter	clinical testing
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
PreventionGenetics, part of Exact Sciences	RCV003924850	SCV004739863	pathogenic	SLC25A13-related disorder	2023-11-09	no assertion criteria provided	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.