chr16-72014641-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PP3PP5_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

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

DHODH
NM_001361.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 3.32

Publications

29 publications found

Variant links:

Genes affected

DHODH (HGNC:2867): (dihydroorotate dehydrogenase (quinone)) The protein encoded by this gene catalyzes the fourth enzymatic step, the ubiquinone-mediated oxidation of dihydroorotate to orotate, in de novo pyrimidine biosynthesis. This protein is a mitochondrial protein located on the outer surface of the inner mitochondrial membrane. [provided by RefSeq, Jul 2008]

DHODH Gene-Disease associations (from GenCC):

postaxial acrofacial dysostosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

DHODH links:

ENSG00000294600 (HGNC:):

ENSG00000294600 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when Dann, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

PP5

Variant 16-72014641-C-T is Pathogenic according to our data. Variant chr16-72014641-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.2148906). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHODH	NM_001361.5 link	c.403C>T	p.Arg135Cys	missense_variant	Exon 3 of 9	ENST00000219240.9	NP_001352.2	Q02127
DHODH	XM_047433674.1 link	c.319C>T	p.Arg107Cys	missense_variant	Exon 3 of 9		XP_047289630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHODH	ENST00000219240.9 link	c.403C>T	p.Arg135Cys	missense_variant	Exon 3 of 9	1	NM_001361.5	ENSP00000219240.4		Q02127

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000353

AC:

AN:

249496

AF XY:

0.000384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000707

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000458

AC:

669

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

323

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000573

AC:

637

AN:

1112008

Other (OTH)

AF:

0.000348

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

121

162

202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000519

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41562

American (AMR)

AF:

0.000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68018

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000499

Hom.:

Bravo

AF:

0.000669

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000607

AC:

ExAC

AF:

0.000381

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.00107

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Miller syndrome

Pathogenic:6

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Aug 23, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Jan 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 26, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Apr 11, 2024

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PM3 very strong, PP1 supporting, PP3 supporting -

Aug 02, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.033%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.92 (>=0.6, sensitivity 0.72 and precision 0.9)). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016801 /PMID: 19915526). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 29, 2019

Blueprint Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.91

.;D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

.;H;.

PhyloP100

3.3

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.6

.;D;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.97

MVP

0.97

MPC

0.87

ClinPred

0.95

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.84

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over