Submissions for variant NM_001002294.3(FMO3):c.929C>T (p.Ser310Leu)

gnomAD frequency: 0.00006  dbSNP: rs572292275

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778196	SCV000914360	likely pathogenic	Trimethylaminuria	2018-12-07	criteria provided, single submitter	clinical testing	The FMO3 c.929C>T (p.Ser310Leu) missense variant has been reported in three studies in which it was identified in three individuals with trimethylaminuria (Ferriera et al. 2013; Shimizu et al. 2015; Sánchez Guevara et al. 2017). In one individual with a 75% reduction in FMO activity, the p.Ser310Leu variant was identified in cis as part of a complex allele with a second missense variant which was known to have a mild effect on protein function. The complex allele was found in a heterozygous state with a nonsense variant. In a second case, the p.Ser310Leu was found in a compound heterozygous state with the missense variant known to have a mild effect on protein function and in a third case, a 27 month old female with trimethylaminuria was heterozygous for the p.Ser310Leu variant alone. The p.Ser310Leu variant was absent from 200 controls, but is reported at a frequency of 0.001351 in the Ashkenazi Jewish population of the Genome Aggregation Database. There is no functional evidence available for the p.Ser310Leu variant in isolation, however the p.[(Glu158Lys;Ser310Leu)] complex allele demonstrated trimethylamine N-oxygenation activity that was less than 10% of wildtype (Shimizu et al. 2015). Based on the evidence the p.Ser310Leu variant is classified as likely pathogenic for trimethylaminuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252234	SCV002523075	likely pathogenic	See cases	2022-03-28	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2, PM3, BP4
Baylor Genetics	RCV000778196	SCV003836286	likely pathogenic	Trimethylaminuria	2022-03-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003558577	SCV004293818	pathogenic	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 310 of the FMO3 protein (p.Ser310Leu). This variant is present in population databases (rs572292275, gnomAD 0.1%). This missense change has been observed in individual(s) with trimethylaminuria (PMID: 23791655, 28649550, 28743400). 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: 631576). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FMO3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FMO3 function (PMID: 28649550). For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000778196	SCV004807310	likely pathogenic	Trimethylaminuria	2024-03-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004768641	SCV005381586	uncertain significance	not specified	2024-08-02	criteria provided, single submitter	clinical testing	Variant summary: FMO3 c.929C>T (p.Ser310Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251064 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FMO3 causing Trimethylaminuria (0.00012 vs 0.0056), allowing no conclusion about variant significance. c.929C>T has been reported in the literature in heterozygous and compound heterozygous individuals affected with Trimethylaminuria (examples: Ferreira_2013; Guevara_2017, Shimizu_2015), particularly in a Japanese individual the variant was detected in cis with another benign variant p.Glu158Lys as part of haplotype and in trans with a pathogenic variant (Shimizu_2015). These data, however, do not allow any conclusion about variant significance. There was no functional studies reported for the variant in isolation but the complex allele (p.[(Glu158Lys;Ser310Leu)]) had less than 10% of wild-type trimethylamine N-oxygenation activity (Shimizu_2015). The following publications have been ascertained in the context of this evaluation (PMID: 23791655, 28649550, 28743400). ClinVar contains an entry for this variant (Variation ID: 631576). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000778196	SCV005632222	likely pathogenic	Trimethylaminuria	2024-06-19	criteria provided, single submitter	clinical testing