NM_000143.4(FH):c.999C>A (p.Cys333Ter) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 15, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002529840.10

Allele description [Variation Report for NM_000143.4(FH):c.999C>A (p.Cys333Ter)]

NM_000143.4(FH):c.999C>A (p.Cys333Ter)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.999C>A (p.Cys333Ter)

HGVS:

NC_000001.11:g.241504151G>T
NG_012338.1:g.20604C>A
NM_000143.4:c.999C>AMANE SELECT
NP_000134.2:p.Cys333Ter
NP_000134.2:p.Cys333Ter
LRG_504t1:c.999C>A
LRG_504:g.20604C>A
LRG_504p1:p.Cys333Ter
NC_000001.10:g.241667451G>T
NM_000143.3:c.999C>A

Protein change:

C333*

Links:

dbSNP: rs1553341031

NCBI 1000 Genomes Browser:

rs1553341031

Molecular consequence:

NM_000143.4:c.999C>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000756686	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 15, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11865300, 21398687, 31831373, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000756686

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 15, 2023)

germline

clinical testing

PubMed (4)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.

Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, et al.

Nat Genet. 2002 Apr;30(4):406-10. Epub 2002 Feb 25.

PubMed [citation]

PMID:: 11865300

Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.

Gardie B, Remenieras A, Kattygnarath D, Bombled J, Lefèvre S, Perrier-Trudova V, Rustin P, Barrois M, Slama A, Avril MF, Bessis D, Caron O, Caux F, Collignon P, Coupier I, Cremin C, Dollfus H, Dugast C, Escudier B, Faivre L, Field M, Gilbert-Dussardier B, et al.

J Med Genet. 2011 Apr;48(4):226-34. doi: 10.1136/jmg.2010.085068. Epub 2011 Mar 12. Erratum in: J Med Genet. 2011 Aug;48(8):576.

PubMed [citation]

PMID:: 21398687

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000756686.7

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

Description

This sequence change creates a premature translational stop signal (p.Cys333*) in the FH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary leiomyomatosis and renal cell cancer: (PMID: 31831373). ClinVar contains an entry for this variant (Variation ID: 529804). For these reasons, this variant has been 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: Oct 26, 2024

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