ClinVar Miner

Submissions for variant NM_000143.3(FH):c.208G>A (p.Ala70Thr) (rs587782207)

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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 RCV000130874 SCV000185777 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000200494 SCV000854830 likely pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing
GeneDx RCV000200494 SCV000251441 uncertain significance not provided 2018-05-11 criteria provided, single submitter clinical testing This variant is denoted FH c.208G>A at the cDNA level, p.Ala70Thr (A70T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. FH Ala70Thr was observed at an allele frequency of 0.03% (5/17,248) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether FH Ala70Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000462728 SCV000544272 uncertain significance Fumarase deficiency 2016-06-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 70 of the FH protein (p.Ala70Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs587782207, ExAC 0.02%) but has not been reported in the literature in individuals with a FH-related disease. ClinVar contains an entry for this variant (Variation ID: 142062). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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