ClinVar Miner

Submissions for variant NM_000143.3(FH):c.817G>A (p.Ala273Thr) (rs772190176)

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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 RCV000572182 SCV000673383 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000200636 SCV000251421 likely pathogenic not provided 2013-08-15 criteria provided, single submitter clinical testing p.Ala273Thr (GCA>ACA): c.817 G>A in exon 6 of the FH gene (NM_000143.3). The A273T missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative in that a non-polar Alanine residue is replaced by a polar Threonine residue. This change occurs at a highly conserved position in the FH protein, and missense mutations at nearby positions (A274P, G275E) have been reported as pathogenic. Furthermore, multiple in-silico analysis programs predict that A273T is damaging to the FH protein. Therefore, A273T is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s).
Invitae RCV000467363 SCV000544267 uncertain significance Fumarase deficiency 2016-09-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 273 of the FH protein (p.Ala273Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs772190176, ExAC <0.01%) but has not been reported in the literature in individuals with a FH-related disease. ClinVar contains an entry for this variant (Variation ID: 214377). 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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