ClinVar Miner

Submissions for variant NM_001002294.3(FMO3):c.172G>A (p.Val58Ile)

gnomAD frequency: 0.00016  dbSNP: rs144935285
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center RCV000490346 SCV000267324 uncertain significance Trimethylaminuria 2016-03-18 criteria provided, single submitter reference population
Fulgent Genetics, Fulgent Genetics RCV000490346 SCV002815746 uncertain significance Trimethylaminuria 2022-02-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002515595 SCV003523979 pathogenic not provided 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 58 of the FMO3 protein (p.Val58Ile). This variant is present in population databases (rs144935285, gnomAD 0.5%). This missense change has been observed in individual(s) with clinical features of trimethylaminuria (PMID: 15618671, 22819296, 28392825, 33831674). This variant is also known as p.Val158Ile, G265A. ClinVar contains an entry for this variant (Variation ID: 225365). 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: 15618671, 22819296). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003993893 SCV004813713 uncertain significance not specified 2024-02-13 criteria provided, single submitter clinical testing Variant summary: FMO3 c.172G>A (p.Val58Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251230 control chromosomes, predominantly at a frequency of 0.0042 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in FMO3 causing Trimethylaminuria (0.00035 vs 0.0056), allowing no conclusion about variant significance. c.172G>A has been reported in the literature in individuals affected with Trimethylaminuria (Kim_2017, Shimizu_2021, Shimizu_2012, Kubota_2002). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function indicating changes in protein function (Shimizu_2012, Kubota_2002) . The following publications have been ascertained in the context of this evaluation (PMID: 28392825, 15618671, 33831674, 22819296). ClinVar contains an entry for this variant (Variation ID: 225365). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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