Submissions for variant NM_000274.4(OAT):c.1249C>T (p.Pro417Ser)

gnomAD frequency: 0.00002  dbSNP: rs763915205

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001990500	SCV002253641	likely pathogenic	Ornithine aminotransferase deficiency	2023-04-06	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro417 amino acid residue in OAT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1737786, 23076989; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OAT protein function. ClinVar contains an entry for this variant (Variation ID: 1466306). This variant has not been reported in the literature in individuals affected with OAT-related conditions. This variant is present in population databases (rs763915205, gnomAD 0.02%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 417 of the OAT protein (p.Pro417Ser).
PreventionGenetics, part of Exact Sciences	RCV003401984	SCV004120435	uncertain significance	OAT-related disorder	2023-05-25	criteria provided, single submitter	clinical testing	The OAT c.1249C>T variant is predicted to result in the amino acid substitution p.Pro417Ser. To our knowledge, this variant has not been reported in the literature. A different substitution of this amino acid (p.Pro417Leu) has been reported in individuals with gyrate atrophy of choroid and retina (Doimo et al. 2012. PubMed ID: 23076989; Brody et al. 1992. PubMed ID: 1737786; Bell et al. 2021. PubMed ID: 33494148). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-126086582-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.