ClinVar Miner

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

dbSNP: rs1569282905
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756453 SCV000884273 uncertain significance not provided 2017-12-28 criteria provided, single submitter clinical testing The OTC c.1019C>T; p.Ser340Phe variant is not reported in the medical literature, gene-specific variant databases, or in the ClinVar database. The variant is not listed in the dbSNP variant database or in the general population databases (Exome Variant Server, Genome Aggregation Database). Another variant in the same codon, p.Ser340Pro, is reported in the medical literature in two individuals with OTC deficiency (Martin-Hernandez 2014, Oppliger Leibundgut 1997). The serine at this position is moderately conserved and computational algorithms (PolyPhen2, SIFT) predict the variant is deleterious. Considering available information, the clinical significance of this variant cannot be determined with certainty. References: Martin-Hernandez E et al. Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases. Orphanet J Rare Dis. 2014 Nov 30;9:187. Oppliger Leibundgut E et al. Ornithine transcarbamylase deficiency: ten new mutations and high proportion of de novo mutations in heterozygous females. Hum Mutat. 1997;9(5):409-11.
Invitae RCV001376924 SCV001574124 pathogenic Ornithine carbamoyltransferase deficiency 2022-08-31 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 618259). 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. This variant is not present in population databases (gnomAD no frequency). 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).
Genome-Nilou Lab RCV001376924 SCV002033202 likely pathogenic Ornithine carbamoyltransferase deficiency 2021-11-07 criteria provided, single submitter clinical testing

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