NM_000531.6(OTC):c.622G>A (p.Ala208Thr) AND Ornithine carbamoyltransferase deficiency

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Aug 15, 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:: RCV001218092.15

Allele description [Variation Report for NM_000531.6(OTC):c.622G>A (p.Ala208Thr)]

NM_000531.6(OTC):c.622G>A (p.Ala208Thr)

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.622G>A (p.Ala208Thr)

HGVS:

NC_000023.11:g.38403699G>A
NG_008471.1:g.56217G>A
NM_000531.6:c.622G>AMANE SELECT
NP_000522.3:p.Ala208Thr
LRG_846t1:c.622G>A
LRG_846:g.56217G>A
LRG_846p1:p.Ala208Thr
NC_000023.10:g.38262952G>A
NM_000531.5:c.622G>A
P00480:p.Ala208Thr

Protein change:

A208T

Links:

UniProtKB: P00480#VAR_004908; dbSNP: rs72558416

NCBI 1000 Genomes Browser:

rs72558416

Molecular consequence:

NM_000531.6:c.622G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001389960	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9007316, 9028466, 10799432, 25949836, 26819360, 28492532
SCV001521545	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 7, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002033224	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002557829	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 24, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9007316, 28261508, 34014557, 25741868
SCV005093861	Institute of Immunology and Genetics Kaiserslautern	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005381005	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 15, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 34014557, 9028466, 9007316 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Under recognition of late onset ornithine transcarbamylase deficiency.

Schultz RE, Salo MK.

Arch Dis Child. 2000 May;82(5):390-1.

PubMed [citation]

PMID:: 10799432
PMCID:: PMC1718304

Severe hyperammonemia in late-onset ornithine transcarbamylase deficiency triggered by steroid administration.

Gascon-Bayarri J, Campdelacreu J, Estela J, Reñé R.

Case Rep Neurol Med. 2015;2015:453752. doi: 10.1155/2015/453752. Epub 2015 Apr 9.

PubMed [citation]

PMID:: 25949836
PMCID:: PMC4407407

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001389960.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 208 of the OTC protein (p.Ala208Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 9007316, 9028466, 10799432, 25949836, 26819360). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 97274). 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 with a positive predictive value of 95%. 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

From Baylor Genetics, SCV001521545.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002033224.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557829.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ornithine transcarbamylase deficiency (MIM#311250). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated Aspartate/ornithine carbamoyltransferase, Asp/Orn binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individual and has been reported more than five times as pathogenic in ClinVar. In the literature, this variant is well-reported in patients with ornithine transcarbamylase deficiency and is typically asscoiated with late-onset disease. However, it has also been reported to cause severe disease in childhood (LOVD, PMID: 9007316, 28261508, 34014557). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

From Institute of Immunology and Genetics Kaiserslautern, SCV005093861.1

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

Description

ACMG Criteria: PS4, PM1, PM2_P, PP1, PP3, PP5; Variant was found in hemizygous state

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005381005.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: OTC c.622G>A (p.Ala208Thr) 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 183108 control chromosomes. c.622G>A has been reported in the literature in multiple individuals affected with late-onset Ornithine Transcarbamylase Deficiency (e.g. Toquet_2021, van Diggelen_1996, Ausems_1997). 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: 9028466, 34014557, 9007316). ClinVar contains an entry for this variant (Variation ID: 97274). Based on the evidence outlined above, the variant was 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: Oct 26, 2024

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