rs72556259
Variant summary
Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000531.6(OTC):c.416T>C(p.Leu139Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L139L) has been classified as Likely benign.
Frequency
Consequence
NM_000531.6 missense
Scores
Clinical Significance
Conservation
Publications
- ornithine carbamoyltransferase deficiencyInheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.416T>C | p.Leu139Ser | missense_variant | Exon 5 of 10 | ENST00000039007.5 | NP_000522.3 | |
OTC | NM_001407092.1 | c.416T>C | p.Leu139Ser | missense_variant | Exon 7 of 12 | NP_001394021.1 | ||
OTC | XM_017029556.2 | c.416T>C | p.Leu139Ser | missense_variant | Exon 5 of 9 | XP_016885045.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD4 exome Cov.: 28
GnomAD4 genome Cov.: 24
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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Published functional studies supports this variant is associated with impaired OTC activity (PMID: 37146589); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9266388, 10946359, 28324312, 17565723, 33190319, 37146589) -
Ornithine carbamoyltransferase deficiency Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OTC protein function. ClinVar contains an entry for this variant (Variation ID: 97195). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 9266388, 17565723, 33190319; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 139 of the OTC protein (p.Leu139Ser). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at