ClinVar Miner

Submissions for variant NM_000143.3(FH):c.823G>C (p.Gly275Arg) (rs1060499639)

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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 RCV000494229 SCV000581652 likely pathogenic Hereditary cancer-predisposing syndrome 2015-09-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position,Structural Evidence,Other strong data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000445614 SCV000537246 uncertain significance Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
GeneDx RCV000489286 SCV000577381 uncertain significance not provided 2017-03-31 criteria provided, single submitter clinical testing The G275R variant in the FH gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G275R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at the same residue (G275E) has been reported in a family with cutaneous and uterine leiomyomas, supporting the functional importance of this region of the protein (Smit et al., 2011). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000700426 SCV000829180 uncertain significance Fumarase deficiency 2018-03-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 275 of the FH protein (p.Gly275Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FH-related disease. ClinVar contains an entry for this variant (Variation ID: 393574). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different variant (c.823G>A) giving rise to the same protein effect observed here (p.Gly275Arg) and a different missense substitution at this codon (p.Gly275Glu) have been reported in individuals affected with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 20618355, Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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