NM_000531.6:c.817_819delGAG

Variant names:

• chrX-38408971-AGAG-A
• rs72558452
• NM_000531.6:c.817_819delGAG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000531.6(OTC):​c.817_819delGAG​(p.Glu273del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000461 in 1,084,506 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E273E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: OTC NM_000531.6 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.59
• Publications: 5 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 13 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000531.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-38408971-AGAG-A is Pathogenic according to our data. Variant chrX-38408971-AGAG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 97337.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.817_819delGAG	p.Glu273del	conservative_inframe_deletion	Exon 8 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.817_819delGAG	p.Glu273del	conservative_inframe_deletion	Exon 10 of 12		NP_001394021.1
OTC	XM_017029556.2	c.817_819delGAG	p.Glu273del	conservative_inframe_deletion	Exon 8 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.817_819delGAG	p.Glu273del	conservative_inframe_deletion	Exon 8 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-257146_172-257144delGAG		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183136 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000461 AC: 5 AN: 1084506 Hom.: 0 AF XY: 0.00000281 AC XY: 1 AN XY: 355896

African (AFR) AF: 0.00 AC: 0 AN: 25917

American (AMR) AF: 0.00 AC: 0 AN: 34959

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18866

East Asian (EAS) AF: 0.00 AC: 0 AN: 29211

South Asian (SAS) AF: 0.00 AC: 0 AN: 53967

European-Finnish (FIN) AF: 0.0000250 AC: 1 AN: 39965

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4073

European-Non Finnish (NFE) AF: 0.00000240 AC: 2 AN: 832258

Other (OTH) AF: 0.0000442 AC: 2 AN: 45290

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:8

Jun 26, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM4+PS4_Supporting+PM6_Supporting+PP4 -

Apr 26, 2025

Department of Molecular Genetics, Istishari Arab Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The OTC c.817_819delGAG (p.Glu273del) variant results in an in-frame deletion of a single glutamic acid residue at position 273 of the ornithine transcarbamylase protein. This deletion occurs in a conserved region of the gene and is expected to alter protein structure or function. The variant is observed at an extremely low frequency in the general population (5.5e-06 in 183,136 alleles in gnomAD), supporting PM2_Supporting. It has been reported in multiple unrelated individuals diagnosed with ornithine transcarbamylase deficiency, providing moderate evidence for pathogenicity (PS4_Supporting). Literature sources supporting this include Segues et al. (1996), Arranz et al. (2007), Martin-Hernandez et al. (2014), Gobin-Limballe et al. (2021), and Toquet et al. (2021), with associated publications PMID: 8956045, 17334707, 25433810, 34014569, and 34014557. This variant is also present in ClinVar (Variation ID: 97337) with multiple submissions supporting a pathogenic classification. Given that this is a non-repeat, in-frame deletion affecting a functionally relevant residue, PM4 is also applied. Additionally, the variant has been observed as a likely de novo change in at least one individual with consistent clinical features (PM6_Supporting), and the phenotype observed is highly specific for OTC deficiency (PP4). Based on the ACMG/AMP criteria, this variant is classified as pathogenic (criteria met: PM2_Supporting, PM4, PS4_Supporting, PM6_Supporting, PP4). -

Mar 05, 2024

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.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. -

Sep 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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
PhyloP100		7.6
Mutation Taster		=10/90	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: rs72558452; hg19: chrX-38268224;