NM_000143.3(FH):c.738+2T>C AND Fumarase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 16, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000143.3(FH):c.738+2T>C]


FH:fumarate hydratase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000001.11:g.241508601A>G
  • NG_012338.1:g.16154T>C
  • NM_000143.3:c.738+2T>C
  • LRG_504t1:c.738+2T>C
  • LRG_504:g.16154T>C
  • NC_000001.10:g.241671901A>G
dbSNP: rs1060500901
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000143.3:c.738+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]


Fumarase deficiency (FMRD)
Fumaric aciduria; Fumarate Hydratase Deficiency
MONDO: MONDO:0011730; MedGen: C0342770; Orphanet: 24; OMIM: 606812

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000544260Invitaecriteria provided, single submitter
(Sep 16, 2020)
germlineclinical testing

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

SCV000917375Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Feb 27, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



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.

PubMed [citation]

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]
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000544260.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)


This sequence change affects a donor splice site in intron 5 of the FH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals affected with multiple cutaneous leiomyomas and/or renal cell carcinoma (PMID: 28300276, 26173633, Invitae). Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917375.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


Variant summary: FH c.738+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245936 control chromosomes. To our knowledge, no occurrence of c.738+2T>C in individuals affected with Hereditary Leiomyomatosis and Renal Cell Cancer and no experimental evidence demonstrating its impact on protein function have been reported. However, a different change at the same nucleotide (c.738+2T>A) has been reported in a patient affected with multiple cutaneous leiomyomas. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 23, 2021

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