NM_000531.6:c.67C>T

Variant names:

• chrX-38352763-C-T
• rs72552300
• NM_000531.6:c.67C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000531.6(OTC):​c.67C>T​(p.Arg23*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.99
• Publications: 8 publications found

Genes affected

OTC (HGNC:8512): (ornithine transcarbamylase) This nuclear gene encodes a mitochondrial matrix enzyme. The encoded protein is involved in the urea cycle which functions to detoxify ammonia into urea for excretion. Mutations in this enzyme lead to ornithine transcarbamylase deficiency, which causes hyperammonemia. [provided by RefSeq, May 2022]

OTC Gene-Disease associations (from GenCC):

• ornithine carbamoyltransferase deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 383 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38352763-C-T is Pathogenic according to our data. Variant chrX-38352763-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 97292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.67C>T	p.Arg23*	stop_gained	Exon 1 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.67C>T	p.Arg23*	stop_gained	Exon 3 of 12		NP_001394021.1
OTC	XM_017029556.2	c.67C>T	p.Arg23*	stop_gained	Exon 1 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.67C>T	p.Arg23*	stop_gained	Exon 1 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-313358C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:5

Jul 01, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The OTC c.67C>T; p.Arg23Ter variant (rs72552300) is reported in the literature in individuals affected with ornithine transcarbamylase deficiency (Grompe 1991, Wilnai 2018). This variant is reported in ClinVar (Variation ID: 97292), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Grompe M et al. Improved molecular diagnostics for ornithine transcarbamylase deficiency. Am J Hum Genet. 1991 Feb;48(2):212-22. Wilnai Y et al. Prenatal treatment of ornithine transcarbamylase deficiency. Mol Genet Metab. 2018 Mar;123(3):297-300.

Aug 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg23*) in the OTC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTC are known to be pathogenic (PMID: 10946359, 16786505). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 1671317, 18604903). ClinVar contains an entry for this variant (Variation ID: 97292). For these reasons, this variant has been classified as Pathogenic.

Dec 26, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 13, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The OTC c. 67C>T (p.Arg23*) variant has been reported in three individuals affected with Ornithine transcarbamylase deficiency (Grompe M et al., PMID: 1671317; Lindemann R et al., PMID: 18604903; Martin-Hernandez E et al., PMID: 25433810). This variant has been reported in the ClinVar database as a pathogenic variant by 5 submitters (Variation ID: 97292). This variant is absent from the general population (gnomAD v.4.1), indicating it is not a common variant. This variant leads to a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.

not provided Pathogenic:2

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mar 31, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10946359, 24485820, 1671317, 18604903, 29396029, 9286441, 11793468, 11117428, 25433810, 19138872, 33489762, 33309754, 33272297, 32778825)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		4.0
Vest4		0.77
GERP RS		4.9
PromoterAI		-0.074	Neutral
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72552300; hg19: chrX-38212016; COSMIC: COSV50001813;