NM_001002294.3(FMO3):c.458C>T (p.Pro153Leu) AND Trimethylaminuria

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000017701.40

Allele description [Variation Report for NM_001002294.3(FMO3):c.458C>T (p.Pro153Leu)]

NM_001002294.3(FMO3):c.458C>T (p.Pro153Leu)

Genes:

LOC126805916:BRD4-independent group 4 enhancer GRCh37_chr1:171076844-171078043 [Gene]
FMO3:flavin containing dimethylaniline monoxygenase 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q24.3

Genomic location:

Preferred name:

NM_001002294.3(FMO3):c.458C>T (p.Pro153Leu)

HGVS:

NC_000001.11:g.171107811C>T
NG_012690.1:g.21935C>T
NM_001002294.3:c.458C>TMANE SELECT
NM_001319173.2:c.398C>T
NM_001319174.2:c.269C>T
NM_006894.6:c.458C>T
NP_001002294.1:p.Pro153Leu
NP_001306102.1:p.Pro133Leu
NP_001306103.1:p.Pro90Leu
NP_008825.4:p.Pro153Leu
NC_000001.10:g.171076952C>T
NM_001002294.3:c.458C>T
NM_006894.4:c.458C>T
NM_006894.5:c.458C>T
P31513:p.Pro153Leu

Protein change:

P133L; PRO153LEU

Links:

UniProtKB: P31513#VAR_002424; OMIM: 136132.0004; dbSNP: rs72549326

NCBI 1000 Genomes Browser:

rs72549326

Molecular consequence:

NM_001002294.3:c.458C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001319173.2:c.398C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001319174.2:c.269C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006894.6:c.458C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Trimethylaminuria (TMAU)
Synonyms:: FISH-ODOR SYNDROME; Fish malodor syndrome; Stale fish syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011182; MedGen: C0342739; OMIM: 602079; Human Phenotype Ontology: HP:0003614

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000037978	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000041186	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 11191884, 9398858, 9536088, 20301282
SCV000351243	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Sep 6, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9536088, 11191884, 16601883, 9282831, 20301282, 9398858 Citation Link,
SCV000893233	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004242010	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17531949, 9536088, 9398858 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Compound heterozygosity for missense mutations in the flavin-containing monooxygenase 3 (FM03) gene in patients with fish-odour syndrome.

Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR.

Pharmacogenetics. 2000 Dec;10(9):799-807.

PubMed [citation]

PMID:: 11191884

Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children.

Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA.

J Inherit Metab Dis. 2006 Feb;29(1):162-72.

PubMed [citation]

PMID:: 16601883

See all PubMed Citations (8)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000037978.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a brother and sister with trimethylaminuria (TMAU; 602079), Dolphin et al. (1997) identified a homozygous 551C-T transition in the FMO3 gene, changing a CCC proline triplet at codon 153 to a CTC leucine triplet (P153L). Their unaffected parents and a third sib were heterozygous for the mutation. The authors found the same mutation in 2 other trimethylaminuria kindreds, in which it also cosegregated with the disorder. In the first kindred studied, the leu153 allele was found to carry a polymorphism at codon 158, namely glu158. Among 30 unrelated, non-trimethylaminuric individuals, pro153 was found in all, whereas glu158 and lys158 occurred in frequencies of approximately 50% each.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000041186.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000351243.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The FMO3 c.458C>T (p.Pro153Leu) missense variant is reported widely reported in the literature and is noted to be one of the most common variants in the FMO3 gene associated with disease (Philips et al. 2015). Across a selection of the available literature, the p.Pro153Leu variant was identified in a total of 14 individuals with trimethylaminuria, including eight homozygotes and six compound heterozygotes. Four unaffected family members were identified as heterozygotes for the p.Pro153Leu variant (Dolphin et al. 1997; Treacy et al. 1998; Dolphin et al. 2000; Chalmers et al. 2006). The variant was found in one of 108 control chromosomes, and is reported at a frequency of 0.00337 in the European American population of the Exome Sequencing Project. Functional analysis by several groups demonstrated that the p.Pro153Leu variant abolishes the catalytic activity of FMO3 (Dolphin et al. 1997; Cashman et al. 1997; Treacy et al. 1998). Based on the collective evidence, the p.Pro153Leu variant is classified as pathogenic for trimethylaminuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893233.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004242010.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: FMO3 c.458C>T (p.Pro153Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 251080 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FMO3 causing Trimethylaminuria (0.001 vs 0.0056), allowing no conclusion about variant significance. c.458C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Trimethylaminuria (e.g., Dolphin_1997, Treacy_1998), and the variant has been shown to segregate with disease in related individuals (e.g., Dolphin_1997). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in undetectable or severely reduced (<10%) enzymatic activity relative to the wild type (e.g., Dolphin_1997, Treacy_1998, Yeung_2007). The following publications have been ascertained in the context of this evaluation (PMID: 9398858, 9536088, 17531949). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (pathogenic, n = 3; VUS, n = 1). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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