ClinVar Miner

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

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Total submissions: 5
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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 2018-10-29 criteria provided, single submitter clinical testing The p.A70T variant (also known as c.208G>A), located in coding exon 2 of the FH gene, results from a G to A substitution at nucleotide position 208. The alanine at codon 70 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 2019-12-24 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%). This variant has not been reported in the literature with 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, 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000200494 SCV000854830 likely pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing
Natera, Inc. RCV000462728 SCV001455897 uncertain significance Fumarase deficiency 2020-01-24 no assertion criteria provided clinical testing

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