Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003499934 | SCV005203628 | likely pathogenic | ALG3-congenital disorder of glycosylation | 2025-06-02 | criteria provided, single submitter | clinical testing | Variant summary: ALG3 c.1060C>T (p.Arg354Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 2.4e-05 in 248692 control chromosomes. c.1060C>T has been observed in individual(s) affected with ALG3-congenital disorder of glycosylation (Haeuptle_2009, Farolfi_2021, internal_testing). These data indicate that the variant may be associated with disease. Additionally, another missense variant affecting this amino acid (p.Arg354His) has been determined to be pathogenic in ClinVar, supporting the critical relevance of codon 354 to ALG3 protein functionTo 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: 19862844, 34090370). ClinVar contains an entry for this variant (Variation ID: 2734602). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV003499934 | SCV004293554 | likely pathogenic | ALG3-congenital disorder of glycosylation | 2024-12-13 | criteria provided, single submitter | clinical testing | 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%). 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; internal data). ClinVar contains an entry for this variant (Variation ID: 2734602). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ALG3 protein function with a positive predictive value of 80%. 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. 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. |