ClinVar Miner

Submissions for variant NM_014251.3(SLC25A13):c.2T>C (p.Met1Thr)

gnomAD frequency: 0.00041  dbSNP: rs541276426
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000724177 SCV000224552 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing
Invitae RCV000536292 SCV000646231 uncertain significance Citrin deficiency 2022-08-31 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SLC25A13 mRNA. The next in-frame methionine is located at codon 34. This variant is present in population databases (rs541276426, gnomAD 1.2%), including at least one homozygous and/or hemizygous individual. Disruption of the initiator codon has been observed in individual(s) with citrin deficiency (PMID: 25216257, 27405544). ClinVar contains an entry for this variant (Variation ID: 193371). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects SLC25A13 function (PMID: 23053473). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000724177 SCV000680701 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing The c.2 T>C variant and a missense variant were identified in both an infant with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and the infants unaffected father; the mother was heterozygous for c.2 T>C (Zeng et al. 2014). Found in other patients with NICCD in whom a second SLC25A13 variant was not identified (Treepongkaruna et al. 2012). Functional studies in yeast found c.2 T>C expresses a truncated protein which was not functional; however, no studies have evaluated the effect of this variant in human cells (Wongkittichote et al. 2013). The c.2 T>C variant was found to have a carrier frequency of 1/18 in a Thai population ( Wongkittichote et al. 2013).
Mendelics RCV000987931 SCV001137425 uncertain significance Citrullinemia type I 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001163311 SCV001325334 uncertain significance Citrullinemia type II 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen RCV000724177 SCV001502585 uncertain significance not provided 2020-11-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001331839 SCV001523975 uncertain significance Citrullinemia, type II, adult-onset 2019-02-26 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic RCV000724177 SCV002540876 uncertain significance not provided 2021-05-28 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470789 SCV002768492 uncertain significance Neonatal intrahepatic cholestasis due to citrin deficiency 2022-03-31 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neonatal-onset citrullinemia type II (MIM# 605814) and adult-onset citrullinemia type II (MIM#603471). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (84 heterozygotes, 3 homozygotes). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as VUS in ClinVar. It has also been reported multiple times as homozygous or compound heterozygous in individuals with neonatal intrahepatic cholestasis caused by citrin deficiency (PMID: 23022256, 23067347, 25216257, 27405544, 30887117, 34704407). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in yeast found this variant expresses a truncated protein which was not functional (PMID: 23053473). (SP) 0710 - Another start loss variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change c.2T>A has been reported as VUS in ClinVar. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity RCV000724177 SCV003823365 uncertain significance not provided 2022-11-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155104 SCV003844801 uncertain significance not specified 2023-02-15 criteria provided, single submitter clinical testing Variant summary: SLC25A13 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame methionine is present at codon 34. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 137038 control chromosomes, predominantly at a frequency of 0.012 within the East Asian subpopulation in the gnomAD v2 database, including 1 homozygote. An additional 3 homozygotes are reported in gnomAD v3 database. Nevertheless, c.2T>C has been reported in the literature in compound heterozygous individuals affected with Citrullinemia Type II (e.g. Zhang_2012, Nguyen_2023). Experimental evidence evaluating an impact on protein function in yeast, demonstrated the variant affects function, however, does not allow convincing conclusions about the variant effect in human cells (Wongkittichote_2013). Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance (n=10) and as pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001272105 SCV001453752 uncertain significance Late-onset citrullinemia 2020-09-16 no assertion criteria provided clinical testing
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam RCV002470789 SCV002546531 pathogenic Neonatal intrahepatic cholestasis due to citrin deficiency 2022-06-30 flagged submission clinical testing

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