ClinVar Miner

Submissions for variant NM_000531.6(OTC):c.118C>T (p.Arg40Cys) (rs72554307)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000011760 SCV000756189 likely pathogenic Ornithine carbamoyltransferase deficiency 2019-06-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 40 of the OTC protein (p.Arg40Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with ornithine transcarbamylase deficiency and hyperammonemia (PMID: 23209112, 7860066, Invitae). ClinVar contains an entry for this variant (Variation ID: 11013). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg40His) has been determined to be pathogenic (PMID: 7860066, 8863155, 11793468, 21070677, 23209112). This suggests that the arginine residue is critical for OTC protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000011760 SCV000893833 likely pathogenic Ornithine carbamoyltransferase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000011760 SCV001372246 pathogenic Ornithine carbamoyltransferase deficiency 2020-06-15 criteria provided, single submitter clinical testing Variant summary: OTC c.118C>T (p.Arg40Cys) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyl transferase, carbamoyl-P binding domain (IPR006132) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183119 control chromosomes. c.118C>T has been reported in the literature in individuals affected with later onset Ornithine Transcarbamylase Deficiency and has subsequently cited by others (example, Oppliger Leibundgut_1995, Ploechl_2001, Thurlow_2010, Cavicchi_2014, Caldovic_2015, Ihara_2012). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal OTC activity (Oppliger Leibundgut_1995). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Lastly, another variant at this codon, p.Arg40His has been reported in patients with OTC deficiency supporting the functional relevance of this residue. Based on the evidence outlined above, the variant was classified as pathogenic for fatal late-onset OTC deficiency in boys.
OMIM RCV000011760 SCV000031992 pathogenic Ornithine carbamoyltransferase deficiency 2001-02-01 no assertion criteria provided literature only
GenMed Metabolism Lab RCV000083332 SCV000115418 pathogenic not provided no assertion criteria provided not provided Converted during submission to Pathogenic.

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