Submissions for variant NM_000531.6(OTC):c.409G>A (p.Ala137Thr)

gnomAD frequency: 0.00001  dbSNP: rs72556258

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689450	SCV005184932	uncertain significance	not specified	2024-05-10	criteria provided, single submitter	clinical testing	Variant summary: OTC c.409G>A (p.Ala137Thr) results in a non-conservative amino acid change located in the aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain (IPR006132) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182615 control chromosomes. c.409G>A has been reported in the literature in the heterozygous state in a female and in the hemizygous state in a male whose clinical presentations were not described (Yamaguchi_2006, Sharre_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Ornithine Transcarbamylase Deficiency. At least one in vitro study in COS-7 cells suggests that this variant results in residual enzyme activity of approximately 50% of wildtype and a yeast-based quantitative growth assay suggests that this variant is hypomorhpic and causes a deleterious clinical presentation (e.g. Sharre_2022, Lo_2023). The following publications have been ascertained in the context of this evaluation (PMID: 37146589, 36217298, 16786505). ClinVar contains an entry for this variant (Variation ID: 97193). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GenMed Metabolism Lab	RCV000083428	SCV000115514	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.