ClinVar Miner

Submissions for variant NM_000143.3(FH):c.700A>G (p.Thr234Ala) (rs372505976)

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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 RCV000163828 SCV000214414 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000195694 SCV000251467 pathogenic not provided 2015-09-01 criteria provided, single submitter clinical testing p.Thr234Ala: c.700 A>G. The T234A missense change in the FH gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The T234A mutation was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The T234A mutation is a non-conservative amino acid substitution at a position that is conserved across vertebrate species. In silico analysis predicts this missense change is probably damaging to the protein structure/function. Missense mutations in nearby residues (I228N, I229T, K230R, R233C/H/L, H235R, L244R) have been reported in association with FH-related disease, supporting the functional importance of this region of the protein. Therefore, T234A is considered a disease-causing mutation. The variant is found in FH panel(s).
Invitae RCV000548793 SCV000632487 likely pathogenic Fumarase deficiency 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 234 of the FH protein (p.Thr234Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed predominantly in individuals affected with pheochromocytoma (PCC), including several with malignant/metastatic PCCs. While some of the individuals had clinical features of hereditary leiomyomatosis and renal cell cancer (HLRCC), they did not usually present with classic HLRCC disease (PMID: 30050099, Invitae, external communications). ClinVar contains an entry for this variant (Variation ID: 184555). 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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