NM_000143.4(FH):c.937G>T (p.Glu313Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 11, 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:: RCV000196740.7

Allele description [Variation Report for NM_000143.4(FH):c.937G>T (p.Glu313Ter)]

NM_000143.4(FH):c.937G>T (p.Glu313Ter)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.937G>T (p.Glu313Ter)

Other names:

p.E313*:GAA>TAA

HGVS:

NC_000001.11:g.241504213C>A
NG_012338.1:g.20542G>T
NM_000143.4:c.937G>TMANE SELECT
NP_000134.2:p.Glu313Ter
NP_000134.2:p.Glu313Ter
LRG_504t1:c.937G>T
LRG_504:g.20542G>T
LRG_504p1:p.Glu313Ter
NC_000001.10:g.241667513C>A
NM_000143.3:c.937G>T

Protein change:

E313*

Links:

dbSNP: rs863224001

NCBI 1000 Genomes Browser:

rs863224001

Molecular consequence:

NM_000143.4:c.937G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Mus musculus potassium channel tetramerisation domain containing 17, mRNA (cDNA ...
Mus musculus potassium channel tetramerisation domain containing 17, mRNA (cDNA clone MGC:175686 IMAGE:40131102), complete cds
gi|148878207|gb|BC145799.1|

Nucleotide
Mus musculus cDNA clone IMAGE:9053366
Mus musculus cDNA clone IMAGE:9053366
gi|219519215|gb|BC144818.1|

Nucleotide
PGM1 [Tauraco erythrolophus]
PGM1 [Tauraco erythrolophus]
Gene ID:104380747

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000251473	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Apr 11, 2017)	germline	clinical testing	Citation Link,
SCV003022781	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 11, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11865300, 21398687, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000251473

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Apr 11, 2017)

germline

clinical testing

Citation Link,

SCV003022781

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 11, 2023)

germline

clinical testing

PubMed (3)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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 (3)

Details of each submission

From GeneDx, SCV000251473.15

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

Description

This variant is denoted FH c.937G>T at the cDNA level and p.Glu313Ter (E313X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also published as Glu270Ter using alternate nomenclature, has been reported in at least two individuals with a personal/family history of multiple cutaneous leiomyomas (Gardie 2011). We consider FH Glu313Ter to be pathogenic.

#	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		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003022781.2

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 214415). This variant is also known as c.808G>T (p.Glu270X). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer (PMID: 21398687). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu313*) 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).

#	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: Sep 29, 2024

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