Submissions for variant NM_000531.6(OTC):c.618G>A (p.Met206Ile)

gnomAD frequency: 0.00001  dbSNP: rs72558413

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001724781	SCV001950093	pathogenic	Ornithine carbamoyltransferase deficiency	2021-08-19	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001724781	SCV005398026	likely pathogenic	Ornithine carbamoyltransferase deficiency	2024-09-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ornithine transcarbamylase deficiency (MIM#311250). (I) 0108 - This gene is associated with X-linked disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In males, the phenotypic spectrum can range from lethal neonatal onset to milder forms in late childhood or adulthood while in heterozygous females, the phenotypic spectrum can range from asymptomatic to having recurrent hyperammonemia and/or neurologic impairment depending on the pattern of X-chromosome inactivation in the liver (OMIM, GeneReviews). In addition, individuals with pathogenic variants associated with mild, late-onset disease may experience severe hyperammonemia depending on exposure to strong environmental stressors (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated OTCace domain. (I) 0705 - No comparable variants have previous evidence for pathogenicity. Changes to lysine and arginine have been regarded as pathogenic and reported in individuals with ornithine transcarbamylase deficiency (ClinVar). However, these changes are not regarded as comparable because they have a higher Grantham score and may have a more deleterious effect. (I) 0803 - This variant has limited previous evidence of pathogenicity. It has been regarded as pathogenic in ClinVar by a diagnostic laboratory. In addition, a different nucleotide substitution resulting in the same amino acid change was detected in a heterozygous baby girl with ornithine transcarbamylase deficiency (PMID: 11793483). Authors suggest mother does not have the variant considering allopurinol test; however, genetic studies were not performed to confirm this result (PMID: 11793483). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Biopsy of patient’s intestinal mucosa has shown only 5% of OTC activity (PMID: 11793483). In addition, yeast complementation assay performed in S. cerevisiae has shown that this variant resulted in decreased yeast growth compared to wild-type (PMID: 37146589). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV001724781	SCV005682891	likely pathogenic	Ornithine carbamoyltransferase deficiency	2024-03-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237953	SCV005884927	uncertain significance	not specified	2024-12-23	criteria provided, single submitter	clinical testing	Variant summary: OTC c.618G>A (p.Met206Ile) results in a conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn binding domain (IPR006131) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183114 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.618G>A in individuals affected with Ornithine Transcarbamylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. In addition, two same amino acid change arising from Met206 have been reported, however the pathogeneicity of such variants have not been established (c.618G>C (p.Met206Ile): apparently VUS; c.618G>T (p.Met206Ile): VUS at our lab). ClinVar contains an entry for this variant (Variation ID: 1297045). Based on the evidence outlined above, the variant was classified as uncertain significance.