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

gnomAD frequency: 0.00054  dbSNP: rs201230446

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000316778	SCV000329336	pathogenic	not provided	2022-12-16	criteria provided, single submitter	clinical testing	Published in vitro assays demonstrate R135C results in a significant decrease in DHO-dependent reductase activity (Fang et al., 2012); 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: 23216091, 27219052, 19915526, 22967083, 22692683, 26633542, 21346561, 27814609, 30487145, 31980526, 33262786, 34426522, 31589614)
Illumina Laboratory Services, 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, Mass General Brigham 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.
Blueprint Genetics	RCV000316778	SCV001832256	likely pathogenic	not provided	2019-09-29	criteria provided, single submitter	clinical testing
Invitae	RCV000316778	SCV002129025	pathogenic	not provided	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 135 of the DHODH protein (p.Arg135Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201230446, ExAC 0.06%). This missense change has been observed in individuals with Miller syndrome (PMID: 19915526, 21346561, 22692683). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16801). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects DHODH function (PMID: 22692683, 22967083). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018292	SCV004029295	pathogenic	Miller syndrome	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: DHODH c.403C>T (p.Arg135Cys) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Dihydroorotate dehydrogenase domain (IPR005720) of 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 0.00035 in 249496 control chromosomes (gnomAD). c.403C>T has been reported in the literature in multiple individuals affected with Miller Syndrome (Ng_2010, Rainger_2012, Bukowska-Olech_2020, Al Kaissi_2011), and some were reported as compound heterozygous with another likely pathogenic variant. These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding substantial reductions in enzymatic activity (Fang_2012, Rainger_2012). The following publications have been ascertained in the context of this evaluation (PMID: 19915526, 22692683, 33262786, 22967083, 21346561). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000018292	SCV000038571	pathogenic	Miller syndrome	2010-01-01	no assertion criteria provided	literature only