Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Baylor Genetics | RCV000003604 | SCV000807228 | pathogenic | ALG12-congenital disorder of glycosylation | 2017-09-01 | criteria provided, single submitter | clinical testing | This mutation has been previously reported as disease-causing and has been found once in our laboratory in trans with a deleterious frameshift mutation in a fetus with cystic hygroma, VSD, diaphragmatic hernia, brain malformations, and micrognathia; a previous fetus was similarly affected (not tested). |
Daryl Scott Lab, |
RCV000003604 | SCV001448619 | pathogenic | ALG12-congenital disorder of glycosylation | 2020-11-11 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV001818120 | SCV002064522 | likely pathogenic | not provided | 2017-10-13 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000003604 | SCV002306517 | pathogenic | ALG12-congenital disorder of glycosylation | 2024-01-21 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 146 of the ALG12 protein (p.Arg146Gln). This variant is present in population databases (rs121907932, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of congenital disorders of glycosylation (PMID: 12217961, 17506107, 30266093, 33461977). 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: 3435). 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 with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ALG12 function (PMID: 12217961). For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000003604 | SCV002598947 | likely pathogenic | ALG12-congenital disorder of glycosylation | 2022-09-07 | criteria provided, single submitter | clinical testing | Variant summary: ALG12 c.437G>A (p.Arg146Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250992 control chromosomes (gnomAD). c.437G>A has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation (Grubenmann_2002, Kranz_2007, Normand_2018, Scott_2022). These data indicate that the variant is likely to be associated with disease. A functional yeast complementation assay showed that the variant had very weak rescue ability in an alg12 deficient yeast strain grown with hygromycin B, indicating loss of function (Grubenmann_2002). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Prevention |
RCV003421901 | SCV004118370 | pathogenic | ALG12-related condition | 2023-01-03 | criteria provided, single submitter | clinical testing | The ALG12 c.437G>A variant is predicted to result in the amino acid substitution p.Arg146Gln. This variant has been reported to be causative for autosomal recessive congenital disorder of glycosylation type 1g (CDG1G; OMIM: #607143; Grubenmann et al. 2002. PubMed ID: 12217961; Kranz et al. 2007. PubMed ID: 17506107; Normand et al. 2018. PubMed ID: 30266093). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-50304114-C-T). Given the evidence, we interpret c.437G>A (p.Arg146Gln) as pathogenic. |
OMIM | RCV000003604 | SCV000023762 | pathogenic | ALG12-congenital disorder of glycosylation | 2007-06-15 | no assertion criteria provided | literature only |