rs72558416

Variant names:

• chrX-38403699-G-A
• rs72558416
• NM_000531.6:c.622G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-38403699-G-A
• chrX-38403699-G-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 17P and 4B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong BS2

The NM_000531.6(OTC):​c.622G>A​(p.Ala208Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,096,505 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A208S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 5 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 6.31
• Publications: 18 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 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000531.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38403699-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2083011.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 266 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 1.3274 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-38403699-G-A is Pathogenic according to our data. Variant chrX-38403699-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 97274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.622G>A	p.Ala208Thr	missense_variant	Exon 6 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.622G>A	p.Ala208Thr	missense_variant	Exon 8 of 12		NP_001394021.1
OTC	XM_017029556.2	c.622G>A	p.Ala208Thr	missense_variant	Exon 6 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.622G>A	p.Ala208Thr	missense_variant	Exon 6 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-262422G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000821 AC: 9 AN: 1096505 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 5 AN XY: 361931

African (AFR) AF: 0.00 AC: 0 AN: 26355

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 54110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 840591

Other (OTH) AF: 0.00 AC: 0 AN: 46037

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:7

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Apr 26, 2025

Department of Molecular Genetics, Istishari Arab Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant in the OTC gene, c.622G>A (p.Ala208Thr), results in the substitution of alanine by threonine at codon 208. The variant is located within a functionally critical region of the OTC protein and affects a conserved residue (PM1). It was identified in the hemizygous state in a male patient with a phenotype consistent with ornithine transcarbamylase deficiency and was confirmed by Sanger sequencing. Family segregation analysis revealed that the patient's mother is heterozygous for the variant. This variant is absent from population databases, including gnomAD, 1000 Genomes, ESP, and our NGS in-house data from ~1300 ancestry-matched controls (PM2). It has been reported in multiple affected individuals and submitted as pathogenic by multiple independent clinical laboratories in ClinVar (Variation ID: 97274) (PP5). A different amino acid substitution at the same codon was found in ornithine transcarbamylase deficiency patients (PM5). Multiple in silico tools support a deleterious effect (PolyPhen-2: probably damaging; SIFT: deleterious; MutationTaster: disease-causing) (PP3), and the gene has a low rate of benign missense variation with known missense pathogenic mechanisms (PP2). Based on ACMG/AMP criteria, this variant is classified as pathogenic, with supporting evidence: PM1, PM2, PM5, PP2, PP3, PP5. -

Aug 15, 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.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. -

Dec 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 07, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Pathogenic:4

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 08, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies support that this variant is associated with impaired OTC activity (PMID: 37146589); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18071043, 34014569, 34014557, 25026867, 26819360, 28261508, 17437397, 9028466, 28597413, 28324312, 33309754, 33272297, 37146589, 9007316) -

Inborn genetic diseases Pathogenic:1

Nov 17, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.622G>A (p.A208T) alteration is located in exon 6 (coding exon 6) of the OTC gene. This alteration results from a G to A substitution at nucleotide position 622, causing the alanine (A) at amino acid position 208 to be replaced by a threonine (T). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with ornithine transcarbamylase deficiency and segregates with disease in multiple families (van Diggelen, 1996; Schultz, 2000; Cavicchi, 2014; Martín-Hernández, 2014; Gascon-Bayarri, 2015; Sánchez, 2017; Silvera-Ruiz, 2019; Lu, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.90		Gain of ubiquitination at K210 (P = 0.1621);
MVP		1.0
MPC		1.1
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.90
Mutation Taster		=20/80	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: rs72558416; hg19: chrX-38262952; COSMIC: COSV50001314; COSMIC: COSV50001314;