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.241T>C (p.Ser81Pro)

CA412716867

1504390 (ClinVar)

Gene: OTC (HGNC:5009)

Condition: ornithine carbamoyltransferase deficiency (MONDO:0010703)

Inheritance Mode: X-linked inheritance

UUID: 0b1c7ad9-4053-46e0-aaff-aeef80d2e106

Approved on: 2026-05-29

Published on: 2026-09-11

HGVS expressions

NM_000531.6(OTC):c.241T>C (p.Ser81Pro)

NM_000531.6:c.241T>C

NC_000023.11:g.38369820T>C

CM000685.2:g.38369820T>C

NC_000023.10:g.38229073T>C

CM000685.1:g.38229073T>C

NC_000023.9:g.38114017T>C

NG_008471.1:g.22338T>C

ENST00000039007.5:c.241T>C

ENST00000643344.1:c.241T>C

ENST00000039007.4:c.241T>C

ENST00000465127.1:c.172-296301T>C

ENST00000488812.1:n.333T>C

NM_000531.5:c.241T>C

Likely Pathogenic

PP3_Moderate PM2_Supporting PS2 PP4

PM1

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Urea Cycle Disorders VCEP

The NM_000531.6(OTC):c.241T>C variant in OTC is a missense variant predicted to cause substitution of serine by proline at amino acid 81 (p.Ser81Pro). This variant has been reported as a de novo variant (confirmed by parental testing) in one (hemizygous) male individual with biochemical evidence of OTC deficiency (elevated ammonia, normal citrulline, and elevated urine uracil) (PS2, PP4) (PMID: 38802913). It has also been reported in 1 heterozygous female with elevated ammonia without further biochemical testing reported (PMID: 32447331), such that this individual cannot be counted for PP4 and/or PS4 as per UCD VCEP specifications. This variant is absent in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.854, which is between 0.773 and 0.932, and Moderate evidence of impact on OTC/NAGS/CPS1 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for OTC deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Urea Cycle Disorders Variant Curation Expert Panel (OTC specifications version 1.0.0): PS2, PM2_Supporting, PP3, PP4.

PP3_Moderate

The REVEL score is 0.854, which is between ≥0.773 and <0.932, meeting UCD VCEP cutoff for use of PP3_Moderate.

PM2_Supporting

Absent from gnomAD v4.1.0

PS2

Identified in 1 hemizygous male with elevated ammonia and normal citrulline, confirmed de novo via parental testing (PMID: 38802913)

PP4

Identified in 1 hemizygous male with elevated ammonia and normal citrulline (0.5 pts for PP4), confirmed de novo via parental testing (PMID: 38802913). Patient also had elevated urine uracil, but urine orotic acid level was not noted.

PM1

Not in any of the designated critical residues by the UCD VCEP

Curation History

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