ClinVar Miner

Submissions for variant NM_001361.5(DHODH):c.403C>T (p.Arg135Cys) (rs201230446)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000316778 SCV000329336 pathogenic not provided 2018-11-26 criteria provided, single submitter clinical testing The R135C pathogenic variant in the DHODH gene has been reported previously in Miller syndrome, in affected individuals who were compound heterozygous for the R135C variant and another variant (Ng et al., 2010; Rainger et al., 2012). The R135C variant was not observed at any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R135C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Fang et al. (2012) report that the R135C variant lies at the ubiquinone-binding site, is protein stable, however possessed no enzymatic activity. We interpret R135C as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000018292 SCV000398764 pathogenic Miller syndrome 2017-04-27 criteria provided, single submitter clinical testing The DHODH c.403C>T (p.Arg135Cys) missense variant has been reported in at least three studies in which it is found in a total of five patients with postaxial acrofacial dysostosis (Miller syndrome) in a compound heterozygous state (Ng et al. 2010; Al Kaissi et al. 2011; Rainger et al. 2012). The variant was found in a heterozygous state in two of 137 controls and is reported at a frequency of 0.0006314 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies utilizing in vitro biochemical analysis in HeLa cell lines that stably expressed the variant protein demonstrated reduced activity of the DHODH enzyme compared to wild type (Fang et al. 2012; Rainger et al. 2012). Based on the evidence, the p.Arg135Cys variant is classified as pathogenic for postaxial acrofacial dysostosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000018292 SCV000967609 likely pathogenic Miller syndrome 2018-08-23 criteria provided, single submitter clinical testing The p.Arg135Cys variant in DHODH has been reported in 4 compound heterozygous in dividuals with Miller syndrome (Ng 2010, Al Kaissi 2011, Rainger 2012) and segre gated with disease in 1 affected family member (Rainger 2012). This variant has also been reported in ClinVar (Variation ID 16801). This variant has been identi fied in 0.065% (82/126694) of European chromosomes by the Genome Aggregation Dat abase (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. In vitro functional studies provide some evide nce that the p.Arg135Cys variant may impact protein function (Rainger 2012, Fang 2012); however, these types of assays may not accurately represent biological f unction. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg135Cys variant is likely pathogenic for Mil ler syndrome in an autosomal recessive manner based upon presence in affected in dividuals, low frequency in controls, functional evidence. ACMG/AMP Criteria app lied: PM3_Strong, PM2_Supporting, PP1, PP3.
OMIM RCV000018292 SCV000038571 pathogenic Miller syndrome 2010-01-01 no assertion criteria provided literature only

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