ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1301G>A (p.Cys434Tyr) (rs398123164)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492797 SCV000581667 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078146 SCV000109984 uncertain significance not provided 2013-03-06 criteria provided, single submitter clinical testing
GeneDx RCV000078146 SCV000251432 pathogenic not provided 2017-12-29 criteria provided, single submitter clinical testing The C434Y variant in the FH gene has previously been reported in at least one individual with unilateral pheochromocytoma diagnosed in childhood (Clark et al., 2014). Functional studies showed that C434Y leads to catalytically inactive FH protein (Clark et al., 2014). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C434Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and is not located within a known functional domain. Based on currently available evidence, we consider C434Y to be pathogenic.
Invitae RCV000234386 SCV000283664 pathogenic Fumarase deficiency 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 434 of the FH protein (p.Cys434Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 25004247, Invitae). ClinVar contains an entry for this variant (Variation ID: 92453). An in vitro experimental study has shown that this missense change reduces the catalytic activity of fumarate hydratase relative to the wild-type protein (PMID: 25004247). For these reasons, this variant has been classified as Pathogenic.

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