ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1104_1106delinsACT (p.Met368_Pro369delinsIleLeu) (rs863223987)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198761 SCV000251454 likely pathogenic not provided 2016-08-10 criteria provided, single submitter clinical testing The c.1104_1106delGCCinsACT; The M368I missense change has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, a different missense change at the same amino acid position, M368T, has been reported in association with cutaneous leiomyomatosis (Badeloe et al., 2008). Although the M368I missense change is conservative, as both Methionine and Isoleucine are non-polar amino acids, the substitution occurs at a position that is highly conserved through evolution and alters a residue in the active site of the FH protein (Picaud et al., 2011). Therefore, M368I is a strong candidate for a disease-causing pathogenic variant. The P369L missense change has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, a different missense change at the same amino acid position, P369S, has been reported in a patient with fumaric aciduria who harbored a second pathogenic variant on the other allele (Maradin et al., 2006). The P369L substitution alters a position that is highly conserved through evolution and is located in the active site of the FH protein (Picaud et al., 2011). Although Proline and Leucine are both non-polar amino acids, the substitution of a Proline residue may alter the secondary structure of the protein. Therefore, P369L also is a strong candidate for a disease-causing mutation. The variant is found in FH panel(s).

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