ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 354 of the ALG3 protein (p.Arg354Cys). This variant is present in population databases (rs762510540, gnomAD 0.007%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg354 amino acid residue in ALG3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27172925, 29667327). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 ALG3 protein function. This missense change has been observed in individual(s) with clinical features of ALG3-related conditions and/or congenital disorder of glycosylation (PMID: 19862844, 34090370; Invitae).

Variant summary: ALG3 c.1060C>T (p.Arg354Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248692 control chromosomes. c.1060C>T has been reported in the literature in the compound heterozygous state in individuals affected with ALG3-congenital disorder of glycosylation (e.g. Haeuptle_2009, Farolfi_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another missense variant affecting this amino acid (p.Arg354His CV ID 1053045) has been determined to be pathogenic, supporting the critical relevance of codon 354 to ALG3 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 34090370, 19862844). ClinVar contains an entry for this variant (Variation ID: 2734602). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.