Submissions for variant NM_000531.6(OTC):c.1019C>T (p.Ser340Phe)

dbSNP: rs1569282905

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756453	SCV000884273	likely pathogenic	not provided	2024-10-16	criteria provided, single submitter	clinical testing	The OTC c.1019C>T; p.Ser340Phe variant (rs1569282905, ClinVar Variation ID: 618259) is reported in an individual with ornithine carbamylase deficiency (Lu 2020). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1018T>C, p.Ser340Pro) has been reported in individuals with ornithine carbamylase deficiency (Gobin-Limballe 2021, Oppliger Leibundgut 1997). Complementation assays in yeast suggest Ser340Phe change renders OTC hypomorphic (Lo 2023). Computational analyses predict that this variant is deleterious (REVEL: 0.863). Based on available information, this variant is considered to be likely pathogenic. References: Gobin-Limballe S et al. OTC deficiency in females: Phenotype-genotype correlation based on a 130-family cohort. J Inherit Metab Dis. 2021 Sep. PMID: 34014569. Lo RS et al. The functional impact of 1,570 individual amino acid substitutions in human OTC. Am J Hum Genet. 2023 May 4. PMID: 37146589. Lu D et al. Clinical and molecular characteristics of 69 Chinese patients with ornithine transcarbamylase deficiency. Orphanet J Rare Dis. 2020 Dec 3. PMID: 33272297. Oppliger Leibundgut E et al. Ornithine transcarbamylase deficiency: ten new mutations and high proportion of de novo mutations in heterozygous females. Hum Mutat. 1997 PMID: 9143919.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376924	SCV001574124	pathogenic	Ornithine carbamoyltransferase deficiency	2022-08-31	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OTC protein function. This variant disrupts the p.Ser340 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 9143919), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 618259). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 340 of the OTC protein (p.Ser340Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 33272297; Invitae; external communication). In at least one individual the variant was observed to be de novo.
Genome-Nilou Lab	RCV001376924	SCV002033202	likely pathogenic	Ornithine carbamoyltransferase deficiency	2021-11-07	criteria provided, single submitter	clinical testing