U.S. flag

An official website of the United States government

NM_000531.6(OTC):c.903A>T (p.Leu301Phe) AND Ornithine carbamoyltransferase deficiency

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Sep 20, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001228473.15

Allele description [Variation Report for NM_000531.6(OTC):c.903A>T (p.Leu301Phe)]

NM_000531.6(OTC):c.903A>T (p.Leu301Phe)

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.903A>T (p.Leu301Phe)
HGVS:
  • NC_000023.11:g.38411897A>T
  • NG_008471.1:g.64415A>T
  • NM_000531.6:c.903A>TMANE SELECT
  • NP_000522.3:p.Leu301Phe
  • LRG_846t1:c.903A>T
  • LRG_846:g.64415A>T
  • LRG_846p1:p.Leu301Phe
  • NC_000023.10:g.38271150A>T
  • NM_000531.5:c.903A>T
  • P00480:p.Leu301Phe
Protein change:
L301F
Links:
UniProtKB: P00480#VAR_012654; dbSNP: rs72558462
NCBI 1000 Genomes Browser:
rs72558462
Molecular consequence:
  • NM_000531.6:c.903A>T - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001400873Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 18, 2022)
germlineclinical testing

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

SCV001442697Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Sep 20, 2023)
germlineclinical testing

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

Citation Link,

SCV002049318ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)
Likely pathogenic
(Jun 15, 2021)
germlineclinical testing

Citation Link,

SCV004209066Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Mar 24, 2023)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update.

Caldovic L, Abdikarim I, Narain S, Tuchman M, Morizono H.

J Genet Genomics. 2015 May 20;42(5):181-94. doi: 10.1016/j.jgg.2015.04.003. Epub 2015 May 19. Review.

PubMed [citation]
PMID:
26059767
PMCID:
PMC4565140

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV001400873.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 301 of the OTC protein (p.Leu301Phe). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu301 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 26059767), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 expected to disrupt OTC protein function. ClinVar contains an entry for this variant (Variation ID: 97350). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 11793483, 22340867; Invitae).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442697.2

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

Description

Variant summary: OTC c.903A>T (p.Leu301Phe) results in a non-conservative amino acid change located in the aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183317 control chromosomes (gnomAD and publication data). c.903A>T has been reported in the literature in hemizygous individuals affected with Ornithine Transcarbamylase Deficiency (e.g. Climent_2002, Morel_2012, Lung_2022). In addition, at least one publication reports the residual OTC activity in the liver of a hemizygous patient as 3% of normal activity (e.g. Climent_2002). These data indicate that the variant is likely associated with disease. Furthermore, a different variant resulting in the same amino acid change (c.903A>C, p.Leu301Phe) has been reported in a male proband with OTD deficiency whose mother was a carrier and his maternal uncle and brother were both affected (Barbosa-Gouveia_2021), providing supporting evidence for a pathogenic role. The following publications have been ascertained in the context of this evaluation (PMID: 11793483, 35949797, 28324312, 22340867, 34440436). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic/likely pathogenic. 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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002049318.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The OTC c.903A>T; p.Leu301Phe variant (rs72558462) is reported in the literature in multiple individuals affected with ornithine transcarbamylase deficiency (Climent 2002, Morel 2012). Functional analyses of the variant protein show residual liver OTC activity of 3% (Capistrano-Estrada 1994, Climent 2002). This variant is also reported in ClinVar (Variation ID: 97350). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.902T>C, p.Leu301Ser) has been reported in an individual with OTC deficiency and is considered disease causing (Caldovic 2015). The leucine at codon 301 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.86). Based on available information, this variant is considered to be likely pathogenic. References: Caldovic L et al. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. J Genet Genomics. 2015 May 20;42(5):181-94. PMID: 26059767. Capistrano-Estrada S et al. Histopathological findings in a male with late-onset ornithine transcarbamylase deficiency. Pediatr Pathol. 1994 Mar-Apr;14(2):235-43. PMID: 8008687. Climent C et al. Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency. Hum Mutat. 2002 Feb;19(2):185-6. PMID: 11793483. Morel N et al. Diagnosis of ornithine transcarbamylase deficiency secondary to p.Leu301Phe mutation in an adult patient. Rev Neurol (Paris). 2012 Mar;168(3):296-7. PMID: 22340867.

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

From Baylor Genetics, SCV004209066.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 14, 2024