ClinVar Miner

Submissions for variant NM_000531.6(OTC):c.829C>T (p.Arg277Trp) (rs72558454)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000083586 SCV000239036 pathogenic not provided 2016-07-28 criteria provided, single submitter clinical testing The R277W missense variants in the OTC gene has been reported previously in several unrelated individuals in association with late-onset OTC deficiency (Finkelstein et al., 1990; Storkanova et al. 2013).
Invitae RCV000011746 SCV001232174 pathogenic Ornithine carbamoyltransferase deficiency 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 277 of the OTC protein (p.Arg277Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with OTC deficiency (PMID: 2347583, 30285816, 7860066, 2037279, 25026867). ClinVar contains an entry for this variant (Variation ID: 10999). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000011746 SCV001338398 pathogenic Ornithine carbamoyltransferase deficiency 2020-02-03 criteria provided, single submitter clinical testing 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.
OMIM RCV000011746 SCV000031974 pathogenic Ornithine carbamoyltransferase deficiency 1990-06-01 no assertion criteria provided literature only
GenMed Metabolism Lab RCV000083586 SCV000115672 pathogenic not provided no assertion criteria provided not provided Converted during submission to Pathogenic.

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