ClinVar Miner

Submissions for variant NM_000274.3(OAT):c.1250C>T (p.Pro417Leu) (rs121965044)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000000180 SCV000914446 pathogenic Ornithine aminotransferase deficiency 2017-04-28 criteria provided, single submitter clinical testing The OAT c.1250C>T (p.Pro417Leu) missense variant has been reported in three studies in which it is found in at least four individuals with ornithine aminotransferase deficiency including in three individuals in a compound heterozygous state, one of whom carried a third suspected benign variant in cis, as well as in one individual who was homozygous for the variant and carried the same presumed benign variant in cis (Brody et al. 1992; Sergouniotis et al. 2012; Doimo et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00023 in the European American population of the Exome Sequencing Project but this is based on two alleles so the variant is presumed to be rare. The variant was expressed independently in Chinese hamster ovary (CHO) cells and yielded low levels of OAT antigen and absence of OAT activity (Brody et al. 1992). The p.Pro417Leu variant was also expressed in yeast and was found to have less than ten percent of OAT activity compared to wild type and failed to act as a functional complement to allow growth of a yeast strain containing a deletion variant of the CargB gene (Doimo et al. 2013). Based on the collective evidence, the p.Pro417Leu variant is classified as pathogenic for ornithine aminotransferase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000552900 SCV000626796 pathogenic Gyrate atrophy 2016-09-20 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 417 of the OAT protein (p.Pro417Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs121965044, ExAC 0.002%). This variant has been reported in the literature in two individuals affected with gyrate atrophy (PMID: 1737786, 23076989). ClinVar contains an entry for this variant (Variation ID: 157). Experimental studies have shown that this missense change affects OAT protein assembly and stability and completely disrupts OAT protein activity PMID: 1737786, 23076989). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000000180 SCV000081960 probable-pathogenic Ornithine aminotransferase deficiency no assertion criteria provided not provided Converted during submission to Likely pathogenic.
OMIM RCV000000180 SCV000020323 pathogenic Ornithine aminotransferase deficiency 1992-02-15 no assertion criteria provided literature only

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