ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1027C>T (p.Arg343Ter) (rs121913122)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130875 SCV000185779 pathogenic Hereditary cancer-predisposing syndrome 2017-09-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000197989 SCV000251428 pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing The R343X nonsense variant has been reported previously using different nomenclature (Tomlinson et al., 2002) and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The presence of this variant is consistent with a risk to develop features associated with HLRCC.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000017622 SCV000537253 pathogenic Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
Invitae RCV000635284 SCV000756681 pathogenic Fumarase deficiency 2018-09-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg343*) in the FH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121913122, ExAC 0.001%). This variant has been reported to segregate with hereditary leiomyomatosis associated with renal cell carcinoma (HLRCC) in a family (PMID: 25477250). It has also been reported in several families with cutaneous and uterine leiomyomata, and renal cell cancer (PMID: 11865300, 21398687, 21404119). This variant is also known as Arg300X and R300X in the literature. ClinVar contains an entry for this variant (Variation ID: 16235). Experimental studies have shown that this nonsense change results in reduced fumarate hydratase activity in human peripheral blood lymphocytes (PMID: 21398687, 16288654 ). Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000197989 SCV000857782 pathogenic not provided 2017-11-13 criteria provided, single submitter clinical testing
OMIM RCV000017622 SCV000037897 pathogenic Multiple cutaneous leiomyomas 2002-04-01 no assertion criteria provided literature only

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