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NM_000531.6(OTC):c.286T>C (p.Ser96Pro) AND Ornithine carbamoyltransferase deficiency

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Sep 8, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV001233433.9

Allele description [Variation Report for NM_000531.6(OTC):c.286T>C (p.Ser96Pro)]

NM_000531.6(OTC):c.286T>C (p.Ser96Pro)

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.286T>C (p.Ser96Pro)
HGVS:
  • NC_000023.11:g.38369865T>C
  • NG_008471.1:g.22383T>C
  • NM_000531.6:c.286T>CMANE SELECT
  • NP_000522.3:p.Ser96Pro
  • LRG_846t1:c.286T>C
  • LRG_846:g.22383T>C
  • LRG_846p1:p.Ser96Pro
  • NC_000023.10:g.38229118T>C
  • NM_000531.5:c.286T>C
Protein change:
S96P
Links:
dbSNP: rs184053962
NCBI 1000 Genomes Browser:
rs184053962
Molecular consequence:
  • NM_000531.6:c.286T>C - 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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001406026Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Sep 8, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004235694Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(May 4, 2023)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Mutation Study of Malaysian Patients with Ornithine Transcarbamylase Deficiency: Clinical, Molecular, and Bioinformatics Analyses of Two Novel Missense Mutations of the OTC Gene.

Ali EZ, Zakaria Y, Mohd Radzi MA, Ngu LH, Jusoh SA.

Biomed Res Int. 2018;2018:4320831. doi: 10.1155/2018/4320831.

PubMed [citation]
PMID:
30175132
PMCID:
PMC6098936

Estimation of the total number of disease-causing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential.

Arranz JA, Riudor E, Marco-MarĂ­n C, Rubio V.

J Inherit Metab Dis. 2007 Apr;30(2):217-26. Epub 2007 Mar 1.

PubMed [citation]
PMID:
17334707
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001406026.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 96 of the OTC protein (p.Ser96Pro). This variant is present in population databases (rs184053962, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of OTC deficiency (PMID: 30175132). ClinVar contains an entry for this variant (Variation ID: 959988). 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. This variant disrupts the p.Ser96 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 17334707), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

From Revvity Omics, Revvity, SCV004235694.1

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

Last Updated: Mar 16, 2024