ClinVar Genomic variation as it relates to human health

Variant summary: ASS1 c.256C>T (p.Arg86Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250884 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ASS1 causing Citrullinemia Type I (4.4e-05 vs 0.0041), allowing no conclusion about variant significance. c.256C>T has been reported in the literature in multiple homozygous patients (Martin-Hernandez_2014, Zielonka_2019), and in at least one compound heterozygous individual in trans from a pathogenic variant (Kobayashi_1991), with Citrullinemia Type I and associated phenotypes. 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 showing residual enzymatic ASS1 activity in a homozygous indivdual was about 5% of wildtype (Zielonka_2019) . Four 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 (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies demonstrate a damaging effect as residual enzymatic activity was reduced to about 20% of wild-type (Zielonka et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24772957, 24508627, 22494545, 12815590, 1943692, 25433810, 19006241, 7977368, 28111830, 31589614, 32778825, 31469252)

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 86 of the ASS1 protein (p.Arg86Cys). This variant is present in population databases (rs121908644, gnomAD 0.02%). This missense change has been observed in individual(s) with citrullinemia type 1 (PMID: 1943692, 25433810). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6332). 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 not expected to disrupt ASS1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 1943692). This variant disrupts the p.Arg86 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12815590). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.