16-72014641-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBP4
The NM_001361.5(DHODH):c.403C>T(p.Arg135Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000463 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001361.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000519 AC: 79AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000353 AC: 88AN: 249496Hom.: 0 AF XY: 0.000384 AC XY: 52AN XY: 135374
GnomAD4 exome AF: 0.000458 AC: 669AN: 1461854Hom.: 0 Cov.: 33 AF XY: 0.000444 AC XY: 323AN XY: 727232
GnomAD4 genome AF: 0.000519 AC: 79AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35AN XY: 74442
ClinVar
Submissions by phenotype
Miller syndrome Pathogenic:4
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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. -
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. -
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. -
not provided Pathogenic:3
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 135 of the DHODH protein (p.Arg135Cys). This variant is present in population databases (rs201230446, gnomAD 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DHODH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DHODH function (PMID: 22692683, 22967083). For these reasons, this variant has been classified as Pathogenic. -
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Published in vitro assays demonstrate R135C results in a significant decrease in DHO-dependent reductase activity (PMID: 22967083); 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, 22692683, 26633542, 27814609, 30487145, 31980526, 33262786, 34426522, 31589614, 21346561, 22967083, 19915526) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at