ClinVar Miner

Submissions for variant NM_000143.3(FH):c.844G>C (p.Gly282Arg)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000808375 SCV000948483 likely pathogenic Fumarase deficiency 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 282 of the FH protein (p.Gly282Arg). 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 been observed in individuals affected with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) (PMID: 28747166, Invitae). It has also been reported on the opposite chromosome (in trans) from a pathogenic variant in an individual with fumarate hydratase deficiency (FHD) (PMID: 28747166). This finding is consistent with autosomal recessive inheritance for FHD, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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