Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000017707 | SCV000915306 | uncertain significance | Trimethylaminuria | 2017-04-27 | criteria provided, single submitter | clinical testing | The FMO3 c.1302G>A (p.Met434Ile) missense variant has been reported in one study in which it is found in one patient with trimethylaminuia in a compound heterozygous state and in an unaffected parent in a heterozygous state (Dolphin et al. 2000). Both individuals also carried another missense variant in cis with the p.Met434Ile variant. Control data are unavailable for this variant, which is reported at a frequency of 0.00032 in the South Asian population of the Genome Aggregation Database. Expression analysis in insect cells showed that presence of the p.Met434Ile variant resulted in significantly reduced catalytic activity of the enzyme compared to wild type. Based on the limited evidence, the p.Met434Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for trimethylaminuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Labcorp Genetics |
RCV003556037 | SCV004293821 | likely pathogenic | not provided | 2024-01-06 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 434 of the FMO3 protein (p.Met434Ile). This variant is present in population databases (rs72549332, gnomAD 0.03%). This missense change has been observed in individual(s) with trimethylaminuria (PMID: 8401051, 11191884). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 16314). 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 FMO3 protein function. Experimental studies have shown that this missense change affects FMO3 function (PMID: 11191884). 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. |
| OMIM | RCV000017707 | SCV000037984 | pathogenic | Trimethylaminuria | 2000-12-01 | no assertion criteria provided | literature only |