NM_000143.4(FH):c.738+2T>C AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 20, 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:: RCV001577061.6

Allele description [Variation Report for NM_000143.4(FH):c.738+2T>C]

NM_000143.4(FH):c.738+2T>C

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.738+2T>C

HGVS:

NC_000001.11:g.241508601A>G
NG_012338.1:g.16154T>C
NM_000143.4:c.738+2T>CMANE SELECT
LRG_504t1:c.738+2T>C
LRG_504:g.16154T>C
NC_000001.10:g.241671901A>G
NM_000143.3:c.738+2T>C

Links:

dbSNP: rs1060500901

NCBI 1000 Genomes Browser:

rs1060500901

Molecular consequence:

NM_000143.4:c.738+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000544260	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 20, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26173633, 28300276, 16199547, 11865300, 21398687, 28492532
SCV001804381	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 14, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544260

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 20, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001804381

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 14, 2019)

germline

clinical testing

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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel splice site mutation in the fumarate hydratase (FH) gene is associated with multiple cutaneous leiomyomas in a Japanese patient.

Yoshinaga Y, Nakai H, Hayashi R, Ito A, Kariya N, Ito M, Shimomura Y.

J Dermatol. 2016 Jan;43(1):85-91. doi: 10.1111/1346-8138.13019. Epub 2015 Jul 15.

PubMed [citation]

PMID:: 26173633

Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers.

Muller M, Ferlicot S, Guillaud-Bataille M, Le Teuff G, Genestie C, Deveaux S, Slama A, Poulalhon N, Escudier B, Albiges L, Soufir N, Avril MF, Gardie B, Saldana C, Allory Y, Gimenez-Roqueplo AP, Bressac-de Paillerets B, Richard S, Benusiglio PR.

Clin Genet. 2017 Dec;92(6):606-615. doi: 10.1111/cge.13014. Epub 2017 May 2. Erratum in: Clin Genet. 2018 May;93(5):1118. doi: 10.1111/cge.13222.

PubMed [citation]

PMID:: 28300276

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544260.8

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 405921). Disruption of this splice site has been observed in individuals with multiple cutaneous leiomyomas and/or renal cell carcinoma (PMID: 26173633, 28300276; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 of the FH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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

From GeneDx, SCV001804381.1

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

Description

Canonical splice site variant predicted to result in an in-frame deletion of a critical region [Exon 5 with multiple PATH missense variants and the substrate binding region]; Not observed in large population cohorts (Lek et al., 2016)

#	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

Last Updated: Sep 29, 2024

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