ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.252T>G (p.Phe84Leu)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001048418 SCV001212422 pathogenic Amyloidogenic transthyretin amyloidosis 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 84 of the TTR protein (p.Phe84Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This missense variant has been reported in several individuals affected with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 28635949, 8721565, 2046936). This variant is also described as p.Phe64Leu in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Phe84 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10488818, 15820680). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173295 SCV001336379 likely pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing

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