ClinVar Miner

Submissions for variant NM_000143.3(FH):c.947C>A (p.Ala316Asp) (rs863224002)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000494152 SCV000581643 likely pathogenic Hereditary cancer-predisposing syndrome 2016-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000199702 SCV000251475 likely pathogenic not provided 2018-03-08 criteria provided, single submitter clinical testing This variant is denoted FH c.947C>A at the cDNA level, p.Ala316Asp (A316D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCT>GAT). Using alternate nomenclature, this variant would be defined as FH Ala273Asp. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FH Ala316Asp was not observed in large population cohorts (Lek 2016). Although this variant is not located in a known functional domain, missense variants at several surrounding residues have been reported in hereditary leiomyomatosis and renal cell cancer (HLRCC) or fumarate hydratase deficiency kindreds and shown to cause decreased FH enzyme activity (Martinez-Mir 2003, Toro 2003, Pithukpakorn 2006, Marque 2010, Gardie 2011, Picaud 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence and internal clinical data, we consider FH Ala316Asp to be a likely pathogenic variant.
Invitae RCV000697340 SCV000825943 likely pathogenic Fumarase deficiency 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 316 of the FH protein (p.Ala316Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families with features consistent with hereditary leiomyomatosis and renal cell cancer (PMID: 28300276, Invitae). ClinVar contains an entry for this variant (Variation ID: 214416). Experimental studies have shown that this missense change exhibits reduced FH activity compared to the wild-type protein (PMID: 28300276). 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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