ClinVar Miner

Submissions for variant NM_000143.3(FH):c.584T>C (p.Met195Thr) (rs863223965)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505795 SCV000251415 likely pathogenic not provided 2017-08-23 criteria provided, single submitter clinical testing This variant is denoted FH c.584T>C at the cDNA level, p.Met195Thr (M195T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). Using alternate nomenclature, this variant would be defined as FH c.455T>C, p.Met152Thr. This variant has been observed in an individual with multiple cutaneous and uterine leiomyomas (Toro 2003). FH Met195Thr has also been reported in a daughter and mother, both affected by multiple large uterine fibroids, and further testing demonstrated decreased fumarate hydratase activity in lymphocytes as well as identified this variant in the homozygous state in a fibroid sample from the daughter (Kubinova 2013). FH Met195Thr was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FH Met195Thr 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 Met195Thr to be a likely pathogenic variant.
Invitae RCV000693506 SCV000821377 likely pathogenic Fumarase deficiency 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 195 of the FH protein (p.Met195Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12772087, Invitae), and two individuals from one family affected with uterine fibroids (PMID: 22764886). This variant is also known as 455T>C (M152T) in the literature. ClinVar contains an entry for this variant (Variation ID: 214373). Experimental studies have shown that this missense change results in reduced fumarate hydratase activity in lymphocytes isolated from an affected individual (PMID: 22764886). 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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