Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000531.6(OTC):c.1025T>C (p.Leu342Pro)

CA412728043

943237 (ClinVar)

Gene: OTC (HGNC:5009)
Condition: ornithine carbamoyltransferase deficiency (MONDO:0010703)
Inheritance Mode: X-linked inheritance
UUID: 9018a567-e5e9-47ce-aa35-592590b6e29d
Approved on: 2026-06-11
Published on: 2026-09-11

HGVS expressions

NM_000531.6:c.1025T>C
NM_000531.6(OTC):c.1025T>C (p.Leu342Pro)
NC_000023.11:g.38421042T>C
CM000685.2:g.38421042T>C
NC_000023.10:g.38280295T>C
CM000685.1:g.38280295T>C
NC_000023.9:g.38165239T>C
NG_008471.1:g.73560T>C
ENST00000039007.5:c.1025T>C
ENST00000643344.1:c.*775T>C
ENST00000039007.4:c.1025T>C
ENST00000465127.1:c.172-245079T>C
NM_000531.5:c.1025T>C
More

Likely Pathogenic

Met criteria codes 3
PP3_Strong PS3_Moderate PM2_Supporting
Not Met criteria codes 9
PS1 BP4 BP1 PP4 PP2 PM5 PM1 BA1 BS1

Evidence Links 1

Expert Panel

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:c.1025T>C variant in OTC is a missense variant predicted to cause substitution of leucine by proline at amino acid 342 (p.Leu342Pro). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a SCORE of 0.958, which is above the threshold of ≥ 0.932 to apply PP3_Strong, evidence that correlates with impact to OTC function (PP3_Strong). Quantitative growth assay in yeast strains showed <5% wild-type growth activity, indicating that this variant impacts protein function (PMID: 37146589) (PS3_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked ornithine carbamoyltransferase deficiency. ACMG/AMP criteria met, as specified by the ClinGen Urea Cycle Disorders VCEP (OTC specifications version 1.0.0): PM2_Supporting, PP3_Strong, PS3_Moderate.
Met criteria codes
PP3_Strong
The REVEL computational prediction analysis tool produced a score of 0.958, which is above the threshold necessary to apply PP3_Strong (≥ 0.932).
PS3_Moderate
Quantitative growth assay in yeast strains showed <5% wild-type growth activity, indicating that this variant impacts protein function (PMID: 37146589) (PS3_Moderate).
PMID: 37146589: shown to result in <5% wild-type OTC growth activity in yeast assay, consistent with impairing protein function PubMed:37146589
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting)
Not Met criteria codes
PS1
No same AA change found
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Patient described by Bernal et al. could possibly have this variant, but there are typos in the article. The variant is named as c.1025T>G (p.Leu342Pro) in Table 2, but c.1025T>G (p.Lys342Pro) in Supplementary Material. It is rather unclear if this is the same variant that is being curated. Maybe contact paper's authors?
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No other MS vrts were found
PM1
This variant does not reside within a region of OTC that is defined as a mutational hotspot or critical functional domain by the ClinGen Urea Cycle Disorders VCEP.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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