ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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).

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

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 database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3.39 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC25A13 causing Citrullinemia Type II phenotype (0.0035). c.2T>C has been reported in the literature in multiple individuals affected with Citrullinemia Type II (e.g. Zhang_2012, Chen_2022, Nguyen_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect in human cells (Wongkittichote_2013). The following publications have been ascertained in the context of this evaluation (PMID: 25216257, 27405544, 31180159, 34800434, 36599957, 23067347, 23053473, 23022256, 35798653). ClinVar contains an entry for this variant (Variation ID: 193371). Based on the evidence outlined above, the variant was classified as uncertain significance.

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.

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.

The SLC25A13 c.2T>C variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in patients with citrin deficiency (Zeng et al. 2014. PubMed ID: 25216257; Lin et al. 2016. PubMed ID: 27405544). Additionally, this variant was reported in a patient with neonatal intrahepatic cholestasis but was also observed in unaffected controls (Treepongkaruna et al. 2012. PubMed ID: 23067347). Functional studies in a yeast model system suggest that the c.2T>C variant produces a non-functional truncated protein product designated p.Met1_Phe34del (Wongkittichote et al. 2013. PubMed ID: 23053473). However, the c.2T>C variant has not been evaluated in human cells. Of note, this variant has been observed with an allele frequency up to ~1.2%, including one homozygote, in a large database of individuals with unknown phenotype. Although we suspect this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.