X-38411952-C-T

Variant names:

• chrX-38411952-C-T
• rs72558473
• NM_000531.6:c.958C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000531.6(OTC):​c.958C>T​(p.Arg320*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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: 1.08

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38411952-C-T is Pathogenic according to our data. Variant chrX-38411952-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 97371.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.958C>T	p.Arg320*	stop_gained	Exon 9 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.958C>T	p.Arg320*	stop_gained	Exon 11 of 12		NP_001394021.1
OTC	XM_017029556.2	c.*91C>T		downstream_gene_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.958C>T	p.Arg320*	stop_gained	Exon 9 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-254169C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000643344.1	n.*708C>T		non_coding_transcript_exon_variant	Exon 10 of 11			ENSP00000496606.1
OTC	ENST00000643344.1	n.*708C>T		3_prime_UTR_variant	Exon 10 of 11			ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:5

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 97371). This premature translational stop signal has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 8829665, 9610619, 17041896, 25433810). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg320*) 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Oct 22, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 28, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OTC c.958C>T (p.Arg320X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183266 control chromosomes. c.958C>T has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency (e.g. Gobin-Limballe_2021). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2023

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant is found at the 3' end of the OTC gene, therefore the resulting mRNA is predicted to escape nonsense-mediated decay. However, nonsense variants located downstream of this variant have been reported as disease-causing variants in the literature (PMID: 11793468). This variant has been previously reported in hemizygous males, as well as symptomatic and asymptomatic heterozygous females (PMID: 8830175, 9610619, 17596675, 25994866, 28887792, 35131284, 25433810, 33190319, 34014569). The c.958C>T (p.Arg320Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, c.958C>T (p.Arg320Ter) is classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Jul 21, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.958C>T (p.R320*) alteration, located in coding exon 9 of the OTC gene, results from a C to T substitution at nucleotide position 958. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 320. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of OTC, is not expected to trigger nonsense-mediated mRNA decay, and a truncated protein could still be expressed (Maquat, 2004). This alteration removes the last 35 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, this alteration and additional truncating alterations downstream of this alteration have been reported in the literature as disease-causing. The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the OTC c.958C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.958C>T (p.R320*) alteration has been reported in multiple, unrelated male patients with OTC deficiency. Female carriers have been reported to be asymptomatic or present with a later onset OTC deficiency (Choi, 2015; Martín-Hernández, 2014; Matsuda, 1997; Rajabi, 2018; Yoo, 1996). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	33
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.12	N
Vest4		0.89
GERP RS		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 47

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

Publications

LitVar

Other links and lift over

dbSNP: rs72558473; hg19: chrX-38271205;