NM_001002294.3(FMO3):c.458C>T (p.Pro153Leu) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 20, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV002223760.4

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002502436	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 17, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 9398858, 17224546, 31589614, 9282831, 16601883, 31240165, 31980526, 21422137, 25870212, 29555771, 9536088, 17531949, 25741868
SCV003251245	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 8, 2022)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 8401051, 11191884, 12893987, 16601883, 17224546, 21422137, 31240165, 9282831, 9398858, 9536088, 17531949, 28492532
SCV004226538	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 20, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16601883, 17224546, 17531949, 21422137, 31240165, 33473342, 9398858, 9536088, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002502436

AiLife Diagnostics, AiLife Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 17, 2022)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV003251245

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 8, 2022)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV004226538

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 20, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.

Capalbo A, Valero RA, Jimenez-Almazan J, Pardo PM, Fabiani M, Jiménez D, Simon C, Rodriguez JM.

PLoS Genet. 2019 Oct;15(10):e1008409. doi: 10.1371/journal.pgen.1008409.

PubMed [citation]

PMID:: 31589614
PMCID:: PMC6797235

Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.

Hou YC, Yu HC, Martin R, Cirulli ET, Schenker-Ahmed NM, Hicks M, Cohen IV, Jönsson TJ, Heister R, Napier L, Swisher CL, Dominguez S, Tang H, Li W, Perkins BA, Barea J, Rybak C, Smith E, Duchicela K, Doney M, Brar P, Hernandez N, et al.

Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):3053-3062. doi: 10.1073/pnas.1909378117. Epub 2020 Jan 24.

PubMed [citation]

PMID:: 31980526
PMCID:: PMC7022190

See all PubMed Citations (18)

Details of each submission

From AiLife Diagnostics, AiLife Diagnostics, SCV002502436.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (13)

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

From Invitae, SCV003251245.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 153 of the FMO3 protein (p.Pro153Leu). This variant is present in population databases (rs72549326, gnomAD 0.2%). This missense change has been observed in individual(s) with trimethylaminuria (PMID: 8401051, 9398858, 11191884, 12893987, 16601883, 17224546, 21422137, 31240165). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16308). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects FMO3 function (PMID: 9282831, 9398858, 9536088, 17531949). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV004226538.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

PP3, PP4, PM3, PS3, PS4_moderate

#	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		1	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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