ClinVar Miner

Submissions for variant NM_000143.3(FH):c.782G>T (p.Arg261Ile) (rs61736558)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570420 SCV000673394 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000820902 SCV000961638 likely pathogenic Fumarase deficiency 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with isoleucine at codon 261 of the FH protein (p.Arg261Ile). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with fumarate hydratase deficiency (PMID: 23612258). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 485572). 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. 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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