ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1394A>G (p.Tyr465Cys) (rs863224010)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000445635 SCV000537267 likely pathogenic Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
GeneDx RCV000197211 SCV000251485 likely pathogenic not provided 2016-08-29 criteria provided, single submitter clinical testing This variant is denoted FH c.1394A>G at the cDNA level, p.Tyr465Cys (Y465C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). Also reported as Tyr422Cys using alternate nomenclature, this variant was observed in at least two families with multiple cutaneous leiomyomas (Toro 2003), and functional studies show FH Tyr465Cys reduces fumarate hydratase activity compared to control cell lines (Pithukpakorn 2006). FH Tyr465Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FH Tyr465Cys occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider FH Tyr465Cys to be a likely pathogenic variant.
Invitae RCV000706449 SCV000835498 likely pathogenic Fumarase deficiency 2018-03-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 465 of the FH protein (p.Tyr465Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with hereditary leiomyomatosis and renal cell cancer (PMID: 12772087, Invitae). This variant is also known as 1265A>G (Y422C) in the literature. ClinVar contains an entry for this variant (Variation ID: 214425). An experimental study using patient-derived cells has shown that this missense change results in decreased fumarate hydratase enzyme activity when compared with control cells (PMID: 16597677). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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