chr1-45014012-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_000374.5(UROD):c.578G>C(p.Arg193Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R193H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

UROD
NM_000374.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 0.0120

Publications

5 publications found

Variant links:

Genes affected

UROD (HGNC:12591): (uroporphyrinogen decarboxylase) This gene encodes an enzyme in the heme biosynthetic pathway. This enzyme is responsible for catalyzing the conversion of uroporphyrinogen to coproporphyrinogen through the removal of four carboxymethyl side chains. Mutations and deficiency in this enzyme are known to cause familial porphyria cutanea tarda and hepatoerythropoetic porphyria.[provided by RefSeq, Aug 2010]

UROD Gene-Disease associations (from GenCC):

UROD-related inherited porphyria
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
familial porphyria cutanea tarda
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
hepatoerythropoietic porphyria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

UROD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.1116 (below the threshold of 3.09). Trascript score misZ: 1.9283 (below the threshold of 3.09). GenCC associations: The gene is linked to familial porphyria cutanea tarda, UROD-related inherited porphyria, hepatoerythropoietic porphyria.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

PP5

Variant 1-45014012-G-C is Pathogenic according to our data. Variant chr1-45014012-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 254172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROD	NM_000374.5 link	c.578G>C	p.Arg193Pro	missense_variant	Exon 6 of 10	ENST00000246337.9	NP_000365.3	P06132

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROD	ENST00000246337.9 link	c.578G>C	p.Arg193Pro	missense_variant	Exon 6 of 10	1	NM_000374.5	ENSP00000246337.4		P06132

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251414

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000152

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

UROD-related disorder

Pathogenic:1

Dec 12, 2022

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: UROD c.578G>C (p.Arg193Pro) results in a non-conservative amino acid change located in the Uroporphyrinogen decarboxylase (URO-D) domain (IPR000257) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251414 control chromosomes (gnomAD). c.578G>C has been reported in the literature in multiple individuals affected with Porphyria Cutanea Tarda, specifically in individuals of Norwegian ancestry (Phillips_2001, Aarsand_2009). These data indicate that the variant is very likely to be associated with disease. When the variant was expressed in an E. coli expression system, the resulting variant protein was insoluble (Phillips_2001). UROD is typically soluble, strongly suggesting the variant alters the structure of the final protein. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 193 of the UROD protein (p.Arg193Pro). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with porphyria cutanea tarda (PMID: 11719352, 19233912). ClinVar contains an entry for this variant (Variation ID: 254172). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UROD protein function with a negative predictive value of 80%. Studies have shown that this missense change alters UROD gene expression (PMID: 11719352). This variant disrupts the p.Arg193 amino acid residue in UROD. Other variant(s) that disrupt this residue have been observed in individuals with UROD-related conditions (PMID: 19233912), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Familial porphyria cutanea tarda

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.94

D;T;T;D

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.97

D;D;D;.

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Uncertain

2.2

M;.;.;.

PhyloP100

0.012

PrimateAI

Benign

0.22

PROVEAN

Benign

-2.3

N;.;.;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.016

D;.;.;D

Sift4G

Uncertain

0.043

D;.;.;T

Polyphen

0.49

P;.;.;.

Vest4

0.83

MutPred

0.83

Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);.;

MVP

0.95

MPC

0.84

ClinPred

0.30

GERP RS

1.3

Varity_R

0.96

gMVP

0.93

Mutation Taster

=25/75

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over