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NM_000531.6(OTC):c.814GAG[1] (p.Glu273del) AND Ornithine carbamoyltransferase deficiency

Germline classification:
Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:
Mar 5, 2024
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:
RCV000692945.12

Allele description [Variation Report for NM_000531.6(OTC):c.814GAG[1] (p.Glu273del)]

NM_000531.6(OTC):c.814GAG[1] (p.Glu273del)

Gene:
OTC:ornithine transcarbamylase [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
Xp11.4
Genomic location:
Preferred name:
NM_000531.6(OTC):c.814GAG[1] (p.Glu273del)
HGVS:
  • NC_000023.11:g.38408972GAG[1]
  • NG_008471.1:g.61490GAG[1]
  • NM_000531.6:c.814GAG[1]MANE SELECT
  • NM_000531.6:c.817_819delGAG
  • NP_000522.3:p.Glu273del
  • LRG_846t1:c.814GAG[1]
  • LRG_846:g.61490GAG[1]
  • LRG_846p1:p.Glu273del
  • NC_000023.10:g.38268225GAG[1]
  • NC_000023.10:g.38268225_38268227del
  • NM_000531.5:c.817_819del
  • NM_000531.5:c.817_819delGAG
  • NM_000531.6:c.817_819delMANE SELECT
  • NM_000531.6:c.817_819delGAGMANE SELECT
Protein change:
E273del
Links:
dbSNP: rs72558452
NCBI 1000 Genomes Browser:
rs72558452
Molecular consequence:
  • NM_000531.6:c.814GAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
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
SCV000820796Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 15, 2024)
germlineclinical testing

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

SCV001360757Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Mar 5, 2024)
germlineclinical testing

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

Citation Link,

SCV004201313Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Aug 20, 2022)
unknownclinical testing

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

SCV004357055Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Sep 6, 2023)
germlineclinical testing

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

SCV004829119All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely Pathogenic
(Jun 26, 2023)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The E273del variant of uncertain significance of the ornithine transcarbamylase gene - a case for reclassification.

Ducich N, Ah Mew N, Bedoyan JK.

Mol Genet Metab Rep. 2020 Jun;23:100598. doi: 10.1016/j.ymgmr.2020.100598. No abstract available.

PubMed [citation]
PMID:
32420033
PMCID:
PMC7218070

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 (10)

Details of each submission

From Invitae, SCV000820796.4

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

Description

This variant, c.817_819del, results in the deletion of 1 amino acid(s) of the OTC protein (p.Glu273del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs72558452, gnomAD 0.001%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 8956045, 17334707, 25433810, 32420033, 34014557, 34014569). ClinVar contains an entry for this variant (Variation ID: 97337). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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, SCV001360757.5

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

Description

Variant summary: OTC c.817_819delGAG (p.Glu273del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 5.5e-06 in 183136 control chromosomes (gnomAD). c.817_819delGAG has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (Segues_1996, Arranz_2007, Martin-Hernandez_2014, Gobin-Limballe_2021, Toquet_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25433810, 17334707, 8956045, 34014569, 34014557). ClinVar contains an entry for this variant (Variation ID: 97337). 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 Baylor Genetics, SCV004201313.1

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

From Color Diagnostics, LLC DBA Color Health, SCV004357055.1

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

Description

This variant causes an in-frame deletion of one amino acid (glutamic acid) at codon 273 of the OTC protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple male and female individuals affected with late-onset ornithine transcarbamylase deficiency (PMID: 8956045, 10799432, 17334707, 25433810, 34014557, 35145162). This variant has also been observed de novo in a 1.5 month-old female affected with ornithine transcarbamylase deficiency (PMID: 17334707). This variant has been identified in 1/183136 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

From All of Us Research Program, National Institutes of Health, SCV004829119.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

This variant causes an in-frame deletion of one amino acid (glutamic acid) at codon 273 of the OTC protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple male and female individuals affected with late-onset ornithine transcarbamylase deficiency (PMID: 8956045, 17334707, 25433810, 34014557, 35145162). This variant has also been observed de novo in a 1.5 month-old female affected with ornithine transcarbamylase deficiency (PMID: 17334707). This variant has been identified in 1/183136 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Jun 29, 2024