Submissions for variant NM_014251.3(SLC25A13):c.852_855del (p.Met285fs)

dbSNP: rs80338720

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000239614	SCV000267504	pathogenic	Citrullinemia type II	2016-03-18	criteria provided, single submitter	reference population
Eurofins Ntd Llc (ga)	RCV000724667	SCV000331844	pathogenic	not provided	2017-09-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000239614	SCV000470730	pathogenic	Citrullinemia type II	2017-04-27	criteria provided, single submitter	clinical testing	The SLC25A13 c.852_855delTATG (p.Met285ProfsTer2) variant, also referred to in the literature as c.851_854del and c.851del4, is a frameshift variant that leads to premature truncation of the protein, and is one of the most common pathogenic variants in Japanese persons with citrin deficiency. Across a selection of available literature, the p.Met285ProfsTer2 variant has been identified in a homozygous state in 30 patients, in a compound heterozygous state in 27 patients, and in a heterozygous state in two patients in whom a second variant was not identified (Kobayashi et al. 1999; Ohura et al. 2001; Tamamori et al. 2002; Song et al. 2011). The p.Met285ProfsTer2 variant was absent from 127 controls and is reported at a frequency of 0.01515 in the Kinh in Ho Chi Minh City, Vietnam population of the 1000 Genomes Project. Based on the collective evidence and the potential impact of frameshift variants, the p.Met285ProfsTer2 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	RCV000344746	SCV000646232	pathogenic	Citrin deficiency	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met285Profs*2) in the SLC25A13 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A13 are known to be pathogenic (PMID: 10369257, 14680984, 27405544). This variant is present in population databases (rs569808959, gnomAD 0.5%). This premature translational stop signal has been observed in individual(s) with citrin deficiency (PMID: 10369257, 12512993, 23022256, 23067347, 26852511, 27347070, 27405544, 27577219, 27578510). It has also been observed to segregate with disease in related individuals. This variant is also known as c.851del4. ClinVar contains an entry for this variant (Variation ID: 225472). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000006368	SCV001163576	pathogenic	Neonatal intrahepatic cholestasis due to citrin deficiency		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000724667	SCV002020658	pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000724667	SCV002512901	pathogenic	not provided	2020-02-25	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26852511, 27779681, 23022256, 19470249, 17880783, 10369257, 27405544, 12512993, 27347070, 27577219, 29659898, 26858187, 29152073, 29651749, 30591617, 29961769, 16059747, 31620407, 31607264, 29625052, 31845334, 26689913, 33817322, 34426522, 33627582, 31589614, 32289814, 33763395, 33176737, 28981931, 33497767, 33611823)
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	RCV000006368	SCV002546525	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	RCV000239614	SCV002548484	pathogenic	Citrullinemia type II	2022-05-09	criteria provided, single submitter	clinical testing	Variant summary: SLC25A13 c.852_855delTATG (p.Met285ProfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00033 in 251422 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC25A13 causing Citrullinemia Type II (0.00033 vs 0.0011), allowing no conclusion about variant significance. c.852_855delTATG has been widely reported in the literature in multiple individuals affected with Citrullinemia Type II (example, Zong Song_2011). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002503835	SCV002804401	pathogenic	Neonatal intrahepatic cholestasis due to citrin deficiency; Citrullinemia, type II, adult-onset	2021-07-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417766	SCV004116582	pathogenic	SLC25A13-related condition	2022-12-11	criteria provided, single submitter	clinical testing	The SLC25A13 c.852_855delTATG variant is predicted to result in a frameshift and premature protein termination (p.Met285Profs*2). This variant is commonly reported to be causative for citrin deficiency in Asian populations (e.g., Kobayashi et al. 1999. PubMed ID: 10369257, reported as 851del4; Lin et al. 2016. PubMed ID: 27405544, reported as c.851_854del4). Many other predicted loss-of-function variants in SLC25A13 have been reported in association with citrullinemia type 2 and/or neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) (ClinVar database; Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). We classify this variant as pathogenic.
Baylor Genetics	RCV002259321	SCV004203602	pathogenic	Citrullinemia, type II, adult-onset	2023-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000239614	SCV000026549	pathogenic	Citrullinemia type II	2002-11-01	no assertion criteria provided	literature only
OMIM	RCV000006368	SCV000026550	pathogenic	Neonatal intrahepatic cholestasis due to citrin deficiency	2002-11-01	no assertion criteria provided	literature only
GeneReviews	RCV002259321	SCV000041264	not provided	Citrullinemia, type II, adult-onset		no assertion provided	literature only
SingHealth Duke-NUS Institute of Precision Medicine	RCV000006368	SCV000853101	pathogenic	Neonatal intrahepatic cholestasis due to citrin deficiency	2017-06-07	no assertion criteria provided	curation
Natera, Inc.	RCV001272102	SCV001453749	pathogenic	Late-onset citrullinemia	2020-09-16	no assertion criteria provided	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000006368	SCV004800868	pathogenic	Neonatal intrahepatic cholestasis due to citrin deficiency		no assertion criteria provided	clinical testing	PVS1+PM3_VS+PP1_M+PP4