NM_000143.4(FH):c.934T>C (p.Phe312Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 21, 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:: RCV000493445.12

Allele description [Variation Report for NM_000143.4(FH):c.934T>C (p.Phe312Leu)]

NM_000143.4(FH):c.934T>C (p.Phe312Leu)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.934T>C (p.Phe312Leu)

Other names:

p.F312L:TTT>CTT

HGVS:

NC_000001.11:g.241504216A>G
NG_012338.1:g.20539T>C
NM_000143.4:c.934T>CMANE SELECT
NP_000134.2:p.Phe312Leu
NP_000134.2:p.Phe312Leu
LRG_504t1:c.934T>C
LRG_504:g.20539T>C
LRG_504p1:p.Phe312Leu
NC_000001.10:g.241667516A>G
NM_000143.3:c.934T>C

Protein change:

F312L

Links:

dbSNP: rs863224000

NCBI 1000 Genomes Browser:

rs863224000

Molecular consequence:

NM_000143.4:c.934T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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apolipoprotein B, partial [Zapus hudsonius americanus]
apolipoprotein B, partial [Zapus hudsonius americanus]
gi|568402426|gb|AHD25967.1|

Protein
Homo sapiens cDNA clone IMAGE:4076280, containing frame-shift errors
Homo sapiens cDNA clone IMAGE:4076280, containing frame-shift errors
gi|15214799|gb|BC012534.1|

Nucleotide
Tctn2 tectonic family member 2 [Rattus norvegicus]
Tctn2 tectonic family member 2 [Rattus norvegicus]
Gene ID:689779

Gene
689779[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000581679	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21398687, 9635293 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000581679

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Nov 21, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

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

Molecular analysis and prenatal diagnosis of human fumarase deficiency.

Coughlin EM, Christensen E, Kunz PL, Krishnamoorthy KS, Walker V, Dennis NR, Chalmers RA, Elpeleg ON, Whelan D, Pollitt RJ, Ramesh V, Mandell R, Shih VE.

Mol Genet Metab. 1998 Apr;63(4):254-62.

PubMed [citation]

PMID:: 9635293

Details of each submission

From Ambry Genetics, SCV000581679.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.F312L variant (also known as c.934T>C), located in coding exon 7 of the FH gene, results from a T to C substitution at nucleotide position 934. The phenylalanine at codon 312 is replaced by leucine, an amino acid with highly similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with HLRCC-related disease (Ambry internal data). This variant co-segregated with disease in 4/4 individuals from one family tested in our laboratory. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be 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: Nov 3, 2024

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