NM_000531.6(OTC):c.674C>T (p.Pro225Leu) AND Ornithine carbamoyltransferase deficiency

Clinical significance:Pathogenic (Last evaluated: Aug 29, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000011747.14

Allele description [Variation Report for NM_000531.6(OTC):c.674C>T (p.Pro225Leu)]

NM_000531.6(OTC):c.674C>T (p.Pro225Leu)

Gene:
OTC:ornithine transcarbamylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xp11.4
Genomic location:
Preferred name:
NM_000531.6(OTC):c.674C>T (p.Pro225Leu)
HGVS:
  • NC_000023.11:g.38408752C>T
  • NG_008471.1:g.61270C>T
  • NM_000531.6:c.674C>TMANE SELECT
  • NP_000522.3:p.Pro225Leu
  • LRG_846t1:c.674C>T
  • LRG_846:g.61270C>T
  • LRG_846p1:p.Pro225Leu
  • NC_000023.10:g.38268005C>T
  • NM_000531.5:c.674C>T
  • P00480:p.Pro225Leu
Protein change:
P225L; PRO225LEU
Links:
UniProtKB: P00480#VAR_004913; OMIM: 300461.0015; dbSNP: rs67120076
NCBI 1000 Genomes Browser:
rs67120076
Molecular consequence:
  • NM_000531.6:c.674C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Ornithine carbamoyltransferase deficiency (OTCD)
Synonyms:
ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO; Ornithine transcarbamylase deficiency; OTC deficiency; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0010703; MedGen: C0268542; Orphanet: 664; OMIM: 311250

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000031979OMIMno assertion criteria providedPathogenic
(Dec 1, 1991)
germlineliterature only

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

SCV000268692Genomic Research Center,Shahid Beheshti University of Medical Sciencesno assertion criteria providedLikely pathogenic
(May 9, 2016)
inheritedclinical testing

SCV000825697Invitaecriteria provided, single submitter
Pathogenic
(Sep 5, 2018)
germlineclinical testing

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

SCV001364018Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Aug 29, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Persianinheritedno1not providednot providednot providednot providedclinical testing

Citations

PubMed

Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD).

Laemmle A, Gallagher RC, Keogh A, Stricker T, Gautschi M, Nuoffer JM, Baumgartner MR, Häberle J.

PLoS One. 2016;11(4):e0153358. doi: 10.1371/journal.pone.0153358.

PubMed [citation]
PMID:
27070778
PMCID:
PMC4829252

Acute fatal presentation of ornithine transcarbamylase deficiency in a previously healthy male.

Klein OD, Kostiner DR, Weisiger K, Moffatt E, Lindeman N, Goodman S, Tuchman M, Packman S.

Hepatol Int. 2008 Sep;2(3):390-4. doi: 10.1007/s12072-008-9078-x. Epub 2008 May 7. Erratum in: Hepatol Int. 2008 Sep;2(3):395-6.

PubMed [citation]
PMID:
19669271
PMCID:
PMC2716892
See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000031979.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Hentzen et al. (1991) described a family in which a proband and his maternal uncle and maternal great-uncle died in the neonatal period with hyperammonemia caused by OTC deficiency (311250). The mother and maternal grandmother of the proband showed a dramatic increment of urinary orotic acid following protein load, confirming their status as carriers. Using PCR amplification of OTC-specific mRNA derived from a postmortem biopsy of the liver of the proband, Hentzen et al. (1991) found that the MspI site (CCGG) in exon 7 was abolished. They identified a C-T transition in the OTC gene, resulting in a pro225-to-leu (P225L) substitution.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Genomic Research Center,Shahid Beheshti University of Medical Sciences, SCV000268692.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Persian1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritednonot providednot providednot provided1not providednot providednot provided

From Invitae, SCV000825697.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces proline with leucine at codon 225 of the OTC protein (p.Pro225Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with ornithine transcarbamylase (OTC) deficiency in a family (PMID: 1721894) and has been reported in individuals affected with this condition (PMID: 27070778, 9427144, 9286441). ClinVar contains an entry for this variant (Variation ID: 11000). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Other missense substitutions at this codon (p.PRo225Arg and p.Pro225Thr) have been reported in individuals affected with ornithine transcarbamylase (OTC) deficiency (PMID: 9427144, 19669271, 10946359). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001364018.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: OTC c.674C>T (p.Pro225Leu) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182904 control chromosomes (gnomAD). The variant, c.674C>T, has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (OTCD) (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000, Bijarnia-Mahay_2018). Hentzen_1991 reported this variant to segregate with OTCD in one family. These data indicate that the variant is very likely to be associated with disease. Several publications also reported (near) undetectable residual enzyme activities from patient samples (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic (1x) or pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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