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
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 2019-05-14 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26839173, 23757202, 25004247)
Invitae RCV000234386 SCV000283664 pathogenic Fumarase deficiency 2020-09-11 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.
Ambry Genetics RCV000492797 SCV000581667 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-26 criteria provided, single submitter clinical testing The p.C434Y variant (also known as c.1301G>A), located in coding exon 9 of the FH gene, results from a G to A substitution at nucleotide position 1301. The cysteine at codon 434 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was previously seen in a 6-year-old boy who presented with pheochromocytoma and further in vitro analyses showed that this variant is catalytically inactive (Clark GR et al. J. Clin. Endocrinol. Metab. 2014 Oct; 99(10):E2046-50). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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