rs72558454
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000531.6(OTC):c.829C>T(p.Arg277Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R277L) has been classified as Pathogenic.
Frequency
Consequence
NM_000531.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.829C>T | p.Arg277Trp | missense_variant | 8/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.829C>T | p.Arg277Trp | missense_variant | 10/12 | ||
OTC | XM_017029556.2 | c.829C>T | p.Arg277Trp | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.829C>T | p.Arg277Trp | missense_variant | 8/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000643344.1 | c.*579C>T | 3_prime_UTR_variant, NMD_transcript_variant | 9/11 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1097714Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 363108
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:5
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1990 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 11, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 277 of the OTC protein (p.Arg277Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with OTC deficiency (PMID: 2037279, 2347583, 7860066, 25026867, 30285816). ClinVar contains an entry for this variant (Variation ID: 10999). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 03, 2020 | Variant summary: OTC c.829C>T (p.Arg277Trp) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183008 control chromosomes. c.829C>T has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (example, Finkelstein_1990, Morizono_1997, Bijarnia-Mahay_2018, Kim_2006, Lee_2014, Storkanova_2013, Silvera-Ruiz_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 2%-<30% of normal activity OTC'ase activity with a markedly reduced affinity for L-Ornithine (example, Morizono_1997). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | GenMed Metabolism Lab | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2019 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 25994866, 21061009, 25026867, 25525159, 21644234, 23278509, 8365726, 7860066, 29581464, 2347583, 30285816, 2037279, 28324312, 33272297) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at