rs72558495

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_000531.6(OTC):c.1061T>G(p.Phe354Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000423 in 1,181,148 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 6.65

Publications

5 publications found

Variant links:

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

OTC links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.886

PP5

Variant X-38421078-T-G is Pathogenic according to our data. Variant chrX-38421078-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97104.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.1061T>G	p.Phe354Cys	missense_variant	Exon 10 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1 link	c.1061T>G	p.Phe354Cys	missense_variant	Exon 12 of 12		NP_001394021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5 link	c.1061T>G	p.Phe354Cys	missense_variant	Exon 10 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1 link	c.172-245043T>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111431

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000547

AC:

AN:

182812

AF XY:

0.00

show subpopulations

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000374

AC:

AN:

1069717

Hom.:

Cov.:

AF XY:

0.00000296

AC XY:

AN XY:

337543

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25886

American (AMR)

AF:

0.00

AC:

AN:

35164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19186

East Asian (EAS)

AF:

0.00

AC:

AN:

30083

South Asian (SAS)

AF:

0.00

AC:

AN:

53475

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40393

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4066

European-Non Finnish (NFE)

AF:

0.00000490

AC:

AN:

816287

Other (OTH)

AF:

0.00

AC:

AN:

45177

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111431

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33633

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30651

American (AMR)

AF:

0.00

AC:

AN:

10437

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6033

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

53036

Other (OTH)

AF:

0.00

AC:

AN:

1500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency

Pathogenic:5Uncertain:1

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 354 of the OTC protein (p.Phe354Cys). This variant is present in population databases (rs72558495, gnomAD 0.001%). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 9266388, 10869432). ClinVar contains an entry for this variant (Variation ID: 97104). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jun 27, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: OTC c.1061T>G (p.Phe354Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 5.5e-06 in 182812 control chromosomes. c.1061T>G has been observed in individual(s) affected with Ornithine Transcarbamylase Deficiency (e.g. Tuchman_1997, Lee_2000), although one case of an unaffected male individual with the variant has been reported (Roman_2020). Several publications reports experimental evidence evaluating an impact on protein function. The variant resulted in approximately 30-35% activity versus the WT when assayed in vitro (Scharre_2022, Lo_2023), and the most pronounced variant effect was <2% of normal activity in an affected hemizygous individual (Yamaguchi_2006). The following publications have been ascertained in the context of this evaluation (PMID: 10869432, 37146589, 32853555, 36217298, 11793468, 16786505). ClinVar contains an entry for this variant (Variation ID: 97104). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Aug 03, 2017

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The OTC c.1061T>G (p.F354C) variant was previously reported in mild ornithine transcarbamylase deficiency (PMID: 8857803; 16786505). -

May 04, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces phenylalanine with cysteine at the last amino acid codon 354 of the OTC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a 13-year old boy diagnosed with late-onset ornithine transcarbamylase deficiency based on hyperammonemia and 1.8% residual OTC enzyme activity detected in his liver tissue frozen at autopsy (PMID: 8857803). This variant has been observed in a male with first presentation of hyperammonemia at age 14, as well as in his 55-year old, asymptomatic grandfather (PMID: 10946359). OTC enzyme activity was not determined in the proband. This variant has also been observed in a newborn girl diagnosed with phenylketonuria and unaffected with symptoms of ornithine transcarbamylase deficiency (PMID: 32853555). Her grandfather and younger male sibling were unaffected carriers of this variant. This variant has been identified in 1/182812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Sep 01, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

GenMed Metabolism Lab

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 04, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9266388, 8857803, 28324312, 16786505, 32853555, 37146589, 11793468, 10869432, 10946359) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.65

BayesDel_noAF

Pathogenic

0.70

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

PhyloP100

6.6

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.60

MutPred

0.70

Loss of ubiquitination at K353 (P = 0.0709);

MVP

1.0

MPC

1.4

ClinPred

0.85

GERP RS

5.2

Varity_R

0.63

gMVP

0.96

Mutation Taster

=78/22

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over