Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000087036 | SCV000639038 | pathogenic | Congenital disorder of glycosylation type 1E | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 152 of the DPM1 protein (p.Gly152Val). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1 (PMID: 23856421; Invitae). 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: 100636). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DPM1 function (PMID: 23856421, 26729507). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV003148647 | SCV003837073 | pathogenic | not provided | 2023-07-21 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate complete loss of function (Yang et al., 2013; Ardiccioni et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); 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: 31003021, 23856421, 26729507, 28743912) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000087036 | SCV003929337 | likely pathogenic | Congenital disorder of glycosylation type 1E | 2023-04-20 | criteria provided, single submitter | clinical testing | Variant summary: DPM1 c.455G>T (p.Gly152Val) results in a non-conservative amino acid change located in the Glycosyltransferase 2-like domain (IPR001173) of 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 1.6e-05 in 251472 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.455G>T has been reported in the literature in at least one individual affected with Congenital Disorder Of Glycosylation Type 1E (e.g., Yang_2013). Several publications report experimental evidence evaluating an impact on protein function, finding that the variant abolishes binding to DPM3, a non-catalytic subunit of the DPM complex (Yang_2013), reduced activity by 70% in a zebrafish model (Ardiccioni_2016), and abolished activity when the orthologous residue was mutated in a cyanobacterium model (Ardiccioni_2016). Structural modeling studies also show that replacement of the Gly152 residue with a valine is predicted to greatly disrupt the protein structure (e.g., Allen_2017, Gandini_2017). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| OMIM | RCV000087036 | SCV000119850 | pathogenic | Congenital disorder of glycosylation type 1E | 2013-11-01 | no assertion criteria provided | literature only |