Submissions for variant NM_000531.6(OTC):c.663G>T (p.Lys221Asn)

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	RCV002469986	SCV002766070	likely pathogenic	Ornithine carbamoyltransferase deficiency	2022-11-13	criteria provided, single submitter	clinical testing	Variant summary: OTC c.663G>T (p.Lys221Asn) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes the canonical 5' splicing donor site and three predict the variant weakens the same canonical 5' splicing donor site. Two predict the variant creates a new cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 182871 control chromosomes (gnomAD). c.663G>T has been reported in the literature in a female carrier affected with Ornithine Transcarbamylase Deficiency (Kim_2006). These data do not allow any conclusion about variant significance. Experimental evidence evaluating the impact of the variant on protein function using COS-1 cells showed that the variant protein had 0% residual activity (Kim_2006). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV002469986	SCV004299815	pathogenic	Ornithine carbamoyltransferase deficiency	2023-05-13	criteria provided, single submitter	clinical testing	Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects OTC function (PMID: 17041896). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1804689). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 16786505, 17041896; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 221 of the OTC protein (p.Lys221Asn). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon.