ClinVar Miner

Submissions for variant NM_000143.3(FH):c.698G>A (p.Arg233His) (rs121913123)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000493379 SCV000581639 pathogenic Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000017623 SCV000537239 pathogenic Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000196988 SCV000230854 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing
GeneDx RCV000196988 SCV000251419 pathogenic not provided 2018-12-28 criteria provided, single submitter clinical testing This variant is denoted FH c.698G>A at the cDNA level, p.Arg233His (R233H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant, also defined as FH Arg190His using an alternate reference sequence, has been observed in multiple individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC), co-segregating with disease in multiple families (Tomlinson 2002, Alam 2003, Toro 2003, Wei 2006, Raymond 2012, Kopp 2017). FH Arg233His has been described as the most common pathogenic variant in the FH gene and has been reported in various ethnic groups, suggesting that the Arg233 residue is a mutational hotspot (Raymond 2012). FH Arg233His has been associated with reduced fumarase activity in cell lines in both the heterozygous and homozygous states (Tomlinson 2002, Alam 2005, Pollard 2005, Pithukpakorn 2006, Lorenzato 2008). FH Arg233His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the substrate-binding A-site and at a residue that is necessary for proper conformation of the active site (Alam 2005, Pithukpakorn 2006). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
GenomeConnect, ClinGen RCV000017623 SCV000606910 not provided Multiple cutaneous leiomyomas no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000178717 SCV000283675 pathogenic Fumarase deficiency 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 233 of the FH protein (p.Arg233His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121913123, ExAC 0.02%). This variant has been reported in numerous individuals and families affected with hereditary leiomyomatosis and renal cell cancer (PMID: 12772087, 15937070, 20618355, 22127509, 11865300), and was reported to co-segregate with disease in a family (PMID: 12772087). This variant is also known as c.569G>A, p.Arg190His in the literature. ClinVar contains an entry for this variant (Variation ID: 16236). Arg233 is a known mutational hotspot located in the active site of the fumarate hydratase enzyme (PMID: 21445611). Experimental studies in patient-derived cell lines and tumor biopsies have shown that this missense change disrupts FH enzymatic activity (PMID: 11865300, 18313410). Additional in vitro analyses showed that this variant was unable to complement FH-deficient human fibroblasts and also had a dominant-negative effect on endogenous FH enzymatic activity (PMID: 17960613). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000017623 SCV000037898 pathogenic Multiple cutaneous leiomyomas 2006-01-01 no assertion criteria provided literature only

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