Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000018294 | SCV000915732 | uncertain significance | Miller syndrome | 2018-11-19 | criteria provided, single submitter | clinical testing | The DHODH c.454G>A (p.Gly152Arg) variant is a missense variant that has been identified in a compound heterozygous state in two siblings with Miller syndrome, another name for postaxial acrofacial dysostosis (Ng et al. 2010; Roach et al. 2010). This variant was not identified in 237 control individuals but is reported at a frequency of 0.000180 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies performed by Fang et al. (2012) suggested the p.Gly152Arg variant affects protein expression or turnover. In addition, Rainger et al. (2012) determined that the variant enzyme shows reduced activity compared to wild type, although a larger effect was observed using a complementation assay than an in vitro assay of enzyme activity. The evidence for this variant is limited. The p.Gly152Arg variant is thus classified as of a variant of unknown significance but suspicious for pathogenicity for postaxial acrofacial dysostosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Labcorp Genetics |
RCV001851907 | SCV002146744 | uncertain significance | not provided | 2022-06-27 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects DHODH function (PMID: 22692683, 22967083). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16803). This variant is also known as chr16:70608443 G>R. This missense change has been observed in individual(s) with Miller syndrome (PMID: 19915526, 20220176). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs267606766, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 152 of the DHODH protein (p.Gly152Arg). |
| OMIM | RCV000018294 | SCV000038573 | pathogenic | Miller syndrome | 2010-01-01 | no assertion criteria provided | literature only |