Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000534538 | SCV000649500 | pathogenic | ALG12-congenital disorder of glycosylation | 2023-05-08 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 471230). For these reasons, this variant has been classified as Pathogenic. 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 ALG12 protein function. This missense change has been observed in individual(s) with ALG12-congenital disorder of glycosylation (PMID: 31481313). 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. This variant is present in population databases (rs755892540, gnomAD 0.007%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 224 of the ALG12 protein (p.Thr224Met). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001260403 | SCV001437379 | uncertain significance | not specified | 2020-09-30 | criteria provided, single submitter | clinical testing | Variant summary: ALG12 c.671C>T (p.Thr224Met) 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 2e-05 in 251392 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.671C>T has been reported in the literature in two compound heterozygous brothers who were affected with a mild form of ALG12-Congenital Disorder of Glycosylation (Tahata_2019); both of patients carried the variant c.1001delA (p.N334TfsX15) in trans. The siblings had a type I pattern (characteristic for the disease) on carbohydrate-deficient transferrin analysis, however no in vitro functional studies were performed to evaluate the impact of the variant on protein function, therefore these results do not allow convincing conclusions about the variant effect. Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (1x) and VUS (1x). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| OMIM | RCV000534538 | SCV001259210 | pathogenic | ALG12-congenital disorder of glycosylation | 2020-05-21 | no assertion criteria provided | literature only |