NM_000375.3(UROS):c.683C>T (p.Thr228Met) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 27, 2021
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:: RCV001851631.5

Allele description [Variation Report for NM_000375.3(UROS):c.683C>T (p.Thr228Met)]

NM_000375.3(UROS):c.683C>T (p.Thr228Met)

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.683C>T (p.Thr228Met)

HGVS:

NC_000010.11:g.125788983G>A
NG_011557.2:g.39286C>T
NM_000375.3:c.683C>TMANE SELECT
NM_001324036.2:c.764C>T
NM_001324037.2:c.683C>T
NM_001324038.2:c.602C>T
NP_000366.1:p.Thr228Met
NP_001310965.1:p.Thr255Met
NP_001310966.1:p.Thr228Met
NP_001310967.1:p.Thr201Met
LRG_1081t1:c.683C>T
LRG_1081:g.39286C>T
LRG_1081p1:p.Thr228Met
NC_000010.10:g.127477552G>A
NM_000375.2:c.683C>T
NR_136675.2:n.758C>T
NR_136676.2:n.1185C>T
NR_136678.2:n.669C>T
P10746:p.Thr228Met

Protein change:

T201M; THR228MET

Links:

UniProtKB: P10746#VAR_003685; OMIM: 606938.0005; dbSNP: rs121908014

NCBI 1000 Genomes Browser:

rs121908014

Molecular consequence:

NM_000375.3:c.683C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001324036.2:c.764C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001324037.2:c.683C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001324038.2:c.602C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_136675.2:n.758C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_136676.2:n.1185C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_136678.2:n.669C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002232603	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 27, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7860775, 8946173, 12060141, 22816431, 1737856, 30685241, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002232603

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 27, 2021)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Citations

PubMed

Congenital erythropoietic porphyria: identification and expression of 10 mutations in the uroporphyrinogen III synthase gene.

Xu W, Warner CA, Desnick RJ.

J Clin Invest. 1995 Feb;95(2):905-12.

PubMed [citation]

PMID:: 7860775
PMCID:: PMC295583

A systematic analysis of the mutations of the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria.

Fontanellas A, Bensidhoum M, Enriquez de Salamanca R, Moruno Tirado A, de Verneuil H, Ged C.

Eur J Hum Genet. 1996;4(5):274-82.

PubMed [citation]

PMID:: 8946173

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002232603.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces threonine with methionine at codon 228 of the UROS protein (p.Thr228Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs121908014, ExAC 0.02%). This missense change has been observed in individual(s) with congenital erythropoietic porphyria (PMID: 1737856, 7860775, 8946173, 12060141, 22816431). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3754). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects UROS function (PMID: 1737856, 30685241). For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 29, 2024

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