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.498G>T (p.Leu166Phe)

CA10385879

1167469 (ClinVar)

Gene: OTC (HGNC:5009)

Condition: ornithine carbamoyltransferase deficiency (MONDO:0010703)

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

UUID: 153ca2bf-d5f1-4655-af30-15dffe98098a

Approved on: 2026-05-20

Published on: 2026-05-30

HGVS expressions

NM_000531.6:c.498G>T

NM_000531.6(OTC):c.498G>T (p.Leu166Phe)

NC_000023.11:g.38401386G>T

CM000685.2:g.38401386G>T

NC_000023.10:g.38260639G>T

CM000685.1:g.38260639G>T

NC_000023.9:g.38145583G>T

NG_008471.1:g.53904G>T

ENST00000039007.5:c.498G>T

ENST00000643344.1:c.*248G>T

ENST00000039007.4:c.498G>T

ENST00000465127.1:c.172-264735G>T

ENST00000488812.1:n.535G>T

NM_000531.5:c.498G>T

Benign

BA1 BS3_Supporting

PS3 PP4 PP3 PM1 PM5 PM2 BS1 BP4

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.498G>T variant in OTC is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 166 (p.Leu166Phe). To our knowledge, this variant has not been reported in the literature in any individuals with OTC deficiency. The Grpmax Filtering allele frequency in gnomAD v4.1.0 is 0.0001094 (5/45704 alleles) in the Admixed American population, with 21 hemizygotes/homozygotes across all populations which is higher than the ClinGen UCD VCEP threshold (>10 hemizygotes/homozygotes) for BA1, and therefore meets this criterion (BA1). Expression of the variant in yeast resulted in 71.5% which is between 65 and 80% indicating supporting evidence for no impact on OTC function (PMID: 37146589) (BS3_Supporting). The computational predictor REVEL gives a score of 0.57 which is between 0.644 and 0.290 and indicates an uncertain impact on OTC function. In summary, this variant meets the criteria to be classified as benign 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): BA1, BS3_Supporting.

BA1

The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001094 (5/45704 alleles) in the Admixed American population and there are 21 hemizygotes in total.

BS3_Supporting

Growth assay in yeast showed >65% and <80% of wild-type OTC growth activity, indicating that this variant does not impact protein function (PMID: 37146589, BS3_Supporting).

PMID: 37146589: variant shown to result in 71.5% of wild-type growth in yeast assay PubMed:37146589

PS3

PMID: 37146589: variant shown to result in 71.5% (hypomorphic range) of wild-type growth in yeast assay

PP4

No affected individuals with this variant have been reported

PP3

The computational predictor REVEL gives a score of 0.57, which is between 0.644 and 0.290, evidence that indicates an uncertain impact on OTC function.

PM1

Not in any of the designated critical residues per the UCD VCEP specifications

PM5

p.L166S is VUS in ClinVar (ID: 3069921)

PM2

The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001094 (5/45704 alleles) in the Admixed American population and there are 21 hemizygotes in total.

BS1

The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001094 (5/45704 alleles) in the Admixed American population and there are 21 hemizygotes in total.

BP4

The computational predictor REVEL gives a score of 0.57 which is between 0.644 and 0.290, evidence that indicates an uncertain impact on OTC function.

Curation History

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