VCV001457336.11 - ClinVar

NM_000374.5(UROD):c.616C>T (p.Gln206Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000374.5(UROD):c.616C>T (p.Gln206Ter)

Variation ID: 1457336 Accession: VCV001457336.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45014050 (GRCh38) [ NCBI UCSC ] 1: 45479722 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 28, 2022	Oct 8, 2024	Jan 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000374.5:c.616C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000365.3:p.Gln206Ter	nonsense
NM_000374.4:c.616C>T
NR_036510.2:n.678C>T		non-coding transcript variant
NR_158184.1:n.697C>T		non-coding transcript variant
NR_158185.1:n.647C>T		non-coding transcript variant
NC_000001.11:g.45014050C>T
NC_000001.10:g.45479722C>T
NG_007122.2:g.6893C>T
NG_033058.1:g.2306G>A
LRG_1079:g.6893C>T
LRG_1079t1:c.616C>T	LRG_1079p1:p.Gln206Ter

... more HGVS ... less HGVS

Protein change

Q206*

Other names

p.Gln206*

Canonical SPDI

NC_000001.11:45014049:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs771824413 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
UROD		Some evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	139	159

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 10, 2024	RCV001953707.7
Familial porphyria cutanea tarda	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 1, 2023	RCV002246621.5
UROD-related disorder	Pathogenic (1)	no assertion criteria provided	May 3, 2024	RCV004738472.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Familial porphyria cutanea tarda Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002519943.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Jan 10, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002238352.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 1634232‚ 17240319‚ 19233912‚ 19419417‚ 23545314‚ 11295834 Comment: This sequence change creates a premature translational stop signal (p.Gln206) in the UROD gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gln206) in the UROD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UROD are known to be pathogenic (PMID: 1634232, 17240319, 19233912, 19419417, 23545314). This variant is present in population databases (rs771824413, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autosomal dominant porphyria cutanea tarda (PMID: 11295834). ClinVar contains an entry for this variant (Variation ID: 1457336). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial porphyria cutanea tarda Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV003921074.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023	Comment: _x000D_ Criteria applied: PVS1, PS4_MOD
Pathogenic (Dec 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004225768.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (7) PubMed: 11202053‚ 11295834‚ 15186324‚ 16095052‚ 25525159‚ 30514647‚ 34367815 Comment: PS3, PS4_moderate, PVS1 Number of individuals with the variant: 1
Likely pathogenic (Nov 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial porphyria cutanea tarda Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003814181.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (May 03, 2024)	no assertion criteria provided Method: clinical testing	UROD-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362590.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The UROD c.616C>T variant is predicted to result in premature protein termination (p.Gln206). This variant has previously been reported to be causative for porphyria cutanea … (more) The UROD c.616C>T variant is predicted to result in premature protein termination (p.Gln206). This variant has previously been reported to be causative for porphyria cutanea tarda (Anderson HB et al 2021. PubMed ID: 34367815; Cappellini MD et al 2001. PubMed ID: 11295834). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in UROD are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Gln206*) in the UROD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UROD are known to be pathogenic (PMID: 1634232, 17240319, 19233912, 19419417, 23545314). This variant is present in population databases (rs771824413, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autosomal dominant porphyria cutanea tarda (PMID: 11295834). ClinVar contains an entry for this variant (Variation ID: 1457336). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The UROD c.616C>T variant is predicted to result in premature protein termination (p.Gln206*). This variant has previously been reported to be causative for porphyria cutanea tarda (Anderson HB et al 2021. PubMed ID: 34367815; Cappellini MD et al 2001. PubMed ID: 11295834). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in UROD are expected to be pathogenic. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Iatrogenic Iron Overload Causing Porphyria Cutanea Tarda in a Patient With a Rare Nonsense Heterozygous UROD Gene Mutation.	Anderson HB	Cureus	2021	PMID: 34367815
Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations.	Weiss Y	Molecular genetics and metabolism	2019	PMID: 30514647
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Familial porphyria cutanea tarda in Spain: characterization of eight novel mutations in the UROD gene and haplotype analysis of the common p.G281E mutation.	Gómez-Abecia S	Gene	2013	PMID: 23545314
Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives.	Badenas C	Clinical genetics	2009	PMID: 19419417
Familial and sporadic porphyria cutanea tarda: characterization and diagnostic strategies.	Aarsand AK	Clinical chemistry	2009	PMID: 19233912
Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP).	Phillips JD	Translational research : the journal of laboratory and clinical medicine	2007	PMID: 17240319
Expression and characterization of six clinically relevant uroporphyrinogen decarboxylase gene mutations.	Christiansen L	Scandinavian journal of clinical and laboratory investigation	2005	PMID: 16095052
The molecular basis of porphyria cutanea tarda in Chile: identification and functional characterization of mutations in the uroporphyrinogen decarboxylase gene.	Poblete-Gutiérrez P	Experimental dermatology	2004	PMID: 15186324
Seven novel point mutations in the uroporphyrinogen decarboxylase (UROD) gene in patients with familial porphyria cutanea tarda (f-PCT).	Cappellini MD	Human mutation	2001	PMID: 11295834
Uroporphyrinogen decarboxylase gene mutations in Danish patients with porphyria cutanea tarda.	Christiansen L	Scandinavian journal of clinical and laboratory investigation	2000	PMID: 11202053
Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with hepatoerythropoietic porphyria.	de Verneuil H	Human genetics	1992	PMID: 1634232
click to load more click to collapse

Text-mined citations for rs771824413 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000374.5(UROD):c.616C>T (p.Gln206Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs771824413 ...