ClinVar Genomic variation as it relates to human health

Variant summary: SLC25A13 c.1622C>A (p.Ala541Asp) results in a non-conservative amino acid change located in the Mitochondrial carrier protein domain (IPR002067) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes. c.1622C>A has been reported as a compound heterozygous genotype in trans along with a pathogenic variant in SLC25A13 in at-least two siblings affected with neonatal intrahepatic cholestasis caused by citrin deficiency (examples: Song_2008, 2011, Lin_2016, Wang_2022). Heterozygous c.1622C>A has also been reported in 18 of 29364 newborns receiving SLC25A13 genetic testing (Lin_2019). These data indicate that the variant may be associated with Citrullinemia Type II. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31845334, 27405544, 21424115, 19099775, 35085585). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 541 of the SLC25A13 protein (p.Ala541Asp). This missense change has been observed in individual(s) with citrin deficiency (PMID: 19099775, 19185551, 35085585). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2577099). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC25A13 protein function. For these reasons, this variant has been classified as Pathogenic.