Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000531.6(OTC):c.903A>T (p.Leu301Phe)

CA224823

97350 (ClinVar)

Gene: OTC (HGNC:5009)

Condition: ornithine carbamoyltransferase deficiency (MONDO:0010703)

Inheritance Mode: X-linked inheritance (recessive (HP:0001419))

UUID: 441513fd-0c35-4db6-911d-bb1ec0e4d4dd

Approved on: 2026-05-20

Published on: 2026-05-30

HGVS expressions

NM_000531.6:c.903A>T

NM_000531.6(OTC):c.903A>T (p.Leu301Phe)

NC_000023.11:g.38411897A>T

CM000685.2:g.38411897A>T

NC_000023.10:g.38271150A>T

CM000685.1:g.38271150A>T

NC_000023.9:g.38156094A>T

NG_008471.1:g.64415A>T

ENST00000039007.5:c.903A>T

ENST00000643344.1:c.*653A>T

ENST00000039007.4:c.903A>T

ENST00000465127.1:c.172-254224A>T

NM_000531.5:c.903A>T

Likely Pathogenic

PM2_Supporting PP4_Moderate PS4_Moderate PS3_Moderate PP3_Moderate

PM1 PM5

Evidence Links 1

Expert Panel

Urea Cycle Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Urea Cycle Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTC Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Urea Cycle Disorders VCEP

The NM_000531.6:c.903A>T (p.Leu310Phe) variant in OTC affects a base pair that is highly conserved in vertebrates and is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a SCORE of 0.86, which is between 0.773 and 0.932, evidence that correlates with Moderate impact to OTC function (PP3_Moderate). A male patient with this variant has been reported in the literature with hyperammonemia, low citrulline, elevated urine orotic acid, and enzyme activity 3% in patient cells (PP4_Moderate; PMID:8008687, 11793483); the patient had late onset disease. This variant has been reported in two additional male probands observed with late onset OTC deficiency and hyperammonemia. (PS4_Moderate; PMID: 22340867, 35949797). Growth assay in yeast showed 0.029of wild-type OTC growth activity, indicating that this variant impacts protein function (PMID: 37146589, <50% - PS3_Moderate). In summary, this variant meets criteria to be classified as a Likely Pathogenic variant for OTC. OTC-specific ACMG/AMP criteria applied (OTC specifications version 1.0.0): PS4_Moderate, PS3_Moderate, PM2_Supporting, PP3_Moderate, PP4_Moderate.

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting)

PP4_Moderate

A male patient with this variant displayed hyperammonemia, high urinary orotate and undetectable citrulline; patient derived cells had 3% of normal OTC enzyme activity. This is highly specific for late onset OTC deficiency (PP4_Moderate, PMID: 11793483, 2 points).

PS4_Moderate

This variant has been reported in two additional male probands observed with late onset OTC deficiency and hyperammonemia. (PS4_Moderate; PMID: 22340867, 35949797).

PS3_Moderate

Growth assay in yeast showed <50% of wild-type OTC growth activity, indicating that this variant impacts protein function (PMID: 37146589, PS3_Moderate).

The growth rate of yeast cells expressing the L301F human OTC variant was 1.7% of the growth rate of yeast cells expressing wild-type OTC. PubMed:37146589

PP3_Moderate

The computational predictor REVEL gives a SCORE of 0.86, which is between 0.773 and 0.932, evidence that correlates with Moderate impact to OTC function (PP3_Moderate).

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

The current variant is the only variant found in this codon in ClinVar.

Curation History

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