ClinVar Miner

Submissions for variant NM_000143.3(FH):c.554A>G (p.Gln185Arg) (rs779707997)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000494490 SCV000581658 likely pathogenic Hereditary cancer-predisposing syndrome 2015-11-18 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000445603 SCV000537234 likely pathogenic Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
GeneDx RCV000196456 SCV000251493 likely pathogenic not provided 2017-12-28 criteria provided, single submitter clinical testing The Q185R variant in the FH gene has previously been published in association with hereditary leiomyomatosis and renal cell cancer (Tomlinson et al., 2002; Alam et al., 2005; Muller et al., 2017). Alam et al. (2005) reported decreased FH enzyme activity of 46.1% in a heterozygous individual harboring the Q185R variant. This variant is not observed in large population cohorts (Lek et al., 2016). The Q185R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and is located within the enzyme active site (Picaud et al., 2011). In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, the Q185R variant is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.
Invitae RCV000550345 SCV000632470 likely pathogenic Fumarase deficiency 2017-07-18 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 185 of the FH protein (p.Gln185Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 11865300, 28300276, Invitae). This variant is also referred to as p.Gln142Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 214433). Experimental studies have shown that this missense change impacts the FH active site and leads to reduced FH activity (PMID: 11865300, 16237213, 21445611). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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