Submissions for variant NM_001002294.3(FMO3):c.613C>T (p.Arg205Cys)

gnomAD frequency: 0.00004  dbSNP: rs28363549

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001102085	SCV001258733	uncertain significance	Trimethylaminuria	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003574822	SCV004365822	pathogenic	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 205 of the FMO3 protein (p.Arg205Cys). This variant is present in population databases (rs28363549, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of trimethylaminuria (PMID: 15618753, 16858129, 17584019, 28649550, 30351217, 33831674, 35853340). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 21265 C>T. ClinVar contains an entry for this variant (Variation ID: 876845). 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: 17584019, 31401033). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987784	SCV004804425	uncertain significance	not specified	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: FMO3 c.613C>T (p.Arg205Cys) results in a non-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 0.0022 in 1722352 control chromosomes, including 63 homozygotes, predominantly at a frequency of 0.029 within the Japanese subpopulation in the jMorp and gnomAD databases. The observed variant frequency within Japanese control individuals in the jMorp database (Tadaka_2024) is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FMO3 causing Trimethylaminuria phenotype (0.0056), suggesting that the variant is benign when found in the homozygous state. On the other hand, c.613C>T has been reported in the literature in several compound heterozygous individuals affected with Trimethylaminuria (often in trans with a null or complex allele), and the variant was found to segregate with disease in several families (e.g., Fujieda_2003, Shimizu_2019, Shimizu_2021, Shimizu_2022). These data indicate that the pathogenicity of the variant is genotype-dependent, i.e., dependent on the variant observed in trans. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a moderate reduction in the catalytic efficiency of N-oxygenation and S-oxygenation relative to the wild-type enzyme (e.g., Shimizu_2007). The following publications have been ascertained in the context of this evaluation (PMID: 15618753, 17142560, 33831674, 35853340, 30351217, 37930845). ClinVar contains an entry for this variant (Variation ID: 876845). Based on the evidence outlined above, the variant likely represents a hypomorphic allele that may cause disease depending on the variant in trans, therefore, the variant was classified as VUS-possibly pathogenic.