NM_000375.3(UROS):c.244G>T (p.Val82Phe) AND Cutaneous porphyria

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 28, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000003956.13

Allele description [Variation Report for NM_000375.3(UROS):c.244G>T (p.Val82Phe)]

NM_000375.3(UROS):c.244G>T (p.Val82Phe)

Gene:

UROS:uroporphyrinogen III synthase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q26.2

Genomic location:

Preferred name:

NM_000375.3(UROS):c.244G>T (p.Val82Phe)

Other names:

p.Val82Phe

HGVS:

NC_000010.11:g.125815034C>A
NG_011557.2:g.13235G>T
NM_000375.3:c.244G>TMANE SELECT
NM_001324036.2:c.244G>T
NM_001324037.2:c.244G>T
NM_001324038.2:c.244G>T
NM_001324039.2:c.244G>T
NP_000366.1:p.Val82Phe
NP_001310965.1:p.Val82Phe
NP_001310966.1:p.Val82Phe
NP_001310967.1:p.Val82Phe
NP_001310968.1:p.Val82Phe
LRG_1081t1:c.244G>T
LRG_1081:g.13235G>T
LRG_1081p1:p.Val82Phe
NC_000010.10:g.127503603C>A
NM_000375.2:c.244G>T
NR_136676.2:n.500G>T
NR_136677.2:n.500G>T

Protein change:

V82F; VAL82PHE

Links:

OMIM: 606938.0009; dbSNP: rs121908016

NCBI 1000 Genomes Browser:

rs121908016

Molecular consequence:

NM_000375.3:c.244G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001324036.2:c.244G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001324037.2:c.244G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001324038.2:c.244G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001324039.2:c.244G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_136676.2:n.500G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_136677.2:n.500G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Cutaneous porphyria (CEP)
Synonyms:: GUNTHER DISEASE; Porphyria, Erythropoietic; Congenital porphyria; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009902; MedGen: C0162530; Orphanet: 79277; OMIM: 263700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024121	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 1995)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000086781	GeneReviews	no classification provided	not provided	germline	literature only
SCV000361369	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19099412, 8829650, 7860775, 22816431 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000024121

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 1995)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000086781

GeneReviews

no classification provided

not provided

germline

literature only

SCV000361369

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Apr 28, 2017)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Uroporphyrinogen III synthase mutations related to congenital erythropoietic porphyria identify a key helix for protein stability.

Fortian A, Castaño D, Ortega G, Laín A, Pons M, Millet O.

Biochemistry. 2009 Jan 20;48(2):454-61. doi: 10.1021/bi801731q.

PubMed [citation]

PMID:: 19099412

Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene.

Xu W, Astrin KH, Desnick RJ.

Hum Mutat. 1996;7(3):187-92.

PubMed [citation]

PMID:: 8829650

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000024121.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with congenital erythropoietic porphyria (CEP; 263700), Xu et al. (1995) found a val82-to-phe (V82F) missense mutation in the UROS gene. The mutation occurred adjacent to the 5-prime donor site of intron 4 and resulted in approximately 54% aberrantly spliced transcripts with exon 4 deleted. Thus, this novel exonic single-base substitution caused 2 lesions: an amino acid substitution and an aberrantly spliced transcript. The mutation causing V82F is a G-to-T transversion of the last nucleotide of exon 4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000086781.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000361369.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The UROS c.244G>T (p.Val82Phe) missense variant has been reported in two studies in which it was found in two individuals with congenital erythropoietic porphyria including in one patient in a compound heterozygous state and in a second patient in a heterozygous state in whom a second variant was not found (Xu et al. 1995; Katugampola et al. 2012). Control data are not available for this variant which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on two alleles only in a region of good sequence coverage so the variant is presumed rare. In a functional study by Xu et al. (1995) the p.Val82Phe variant enzyme was expressed in E. coli and demonstrated to have 35.8% residual activity and less thermostability compared to wild type. However, in a similar study by Fortian et al. (2009), the variant was shown to have 93.8% of the specific activity of wild type with no decrease in stability. RNA analysis showed that the p.Val82Phe variant produced two RNA species, one of normal size and one shorter product which was the result of a deletion of exon four. The shorter product accounted for 53.8% of the total RNA produced (Xu et al. 1995). The Val82 residue is not conserved between human and mouse (Xu et al. 1996). Based on the evidence, the p.Val82Phe variant is considered to be a variant of unknown significance, but suspicious for pathogenicity for congenital erythropoietic porphyria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 6, 2024

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