ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1127A>C (p.Gln376Pro) (rs200796606)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163798 SCV000214379 pathogenic Hereditary cancer-predisposing syndrome 2018-04-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function by in vitro/ex vivo assay,Structural Evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000034920 SCV000190211 likely benign Fumarase deficiency 2014-06-01 no assertion criteria provided research
GeneDx RCV000199873 SCV000251429 likely pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted FH c.1127A>C at the cDNA level, p.Gln376Pro (Q376P) at the protein level, and results in the change of a Glutamine to a Proline (CAG>CCG). Using alternate nomenclature, this variant is also reported as 998A>C, Gln333Pro, and Gln13Pro. FH Gln376Pro was observed at an allele frequency of 0.01% (13/126688) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). This variant is located within the QTK loop (Pogorelcnik 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. FH Gln376Pro has been reported in six individuals with fumarate hydratase (FH) deficiency from four apparently unrelated families in either the homozygous state or in trans with another FH variant (Zeman 2000, Remes 2004, Phillips 2006, Chan 2017). However the parents and other heterozygous relatives of these individuals were not reported as having features of hereditary leiomyomatosis and renal cell cancer (HLRCC), and the FH Mutation Database notes that FH Gln376Pro is associated with FH deficiency only (Bayley 2008). Based on currently available evidence, we therefore consider FH Gln376Pro to be a variant of uncertain significance with respect to autosomal dominant HLRCC risk and a likely pathogenic variant with respect to autosomal recessive FH deficiency. Fumarate hydratase deficiency is a rare autosomal recessive condition caused by two pathogenic variants (one affecting each allele) of the FH gene. This condition is characterized by excessive urinary excretion of fumurate, neonatal hypotonia, growth and developmental delay, seizures, structural brain malformations, severe neurologic impairment, dysmorphic facial features, and neonatal polycythemia with death typically occurring within the first decade (Gellera 1990, Coughlin 1998, Mroch 2012). If an FH pathogenic variant carrier'spartner is also heterozygous for a pathogenic variant in FH, the risk to have a child with fumarate hydratase deficiency syndrome is 25% for each pregnancy.
GeneReviews RCV000034920 SCV000058527 pathologic Fumarase deficiency 2013-04-04 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000034920 SCV000632435 pathogenic Fumarase deficiency 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 376 of the FH protein (p.Gln376Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is present in population databases (rs200796606, ExAC 0.02%). This variant has been reported as homozygous or compound heterozygous in several families affected with fumarate hydratase deficiency (FHD) (PMID: 10896297, 15221078, 16876016, 28747166). In two of these families, this variant was reported to co-segregate in affected siblings, including a pair of monozygotic twins (PMID: 15221078, 16876016). This variant is also known as 998A>C, Gln13Pro, and Gln333Pro in the literature. ClinVar contains an entry for this variant (Variation ID: 42094). Experimental studies have shown that this missense change leads to reduced fumarate hydratase enzyme activity in cells derived from affected individuals homozygous for this variant (PMID: 17182618, 18313410). In summary, this is a rare missense change that has been reported in several individuals with fumarate hydratase deficiency, and has been shown to disrupt protein function. For these reasons, this variant has been classified as Pathogenic. However, this variant has been observed in unaffected heterozygous individuals, as well as individuals in the population databases, and therefore its association with autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC) is unclear.

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