ClinVar Miner

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

dbSNP: rs2073510805
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001048418 SCV001212422 pathogenic Amyloidogenic transthyretin amyloidosis 2022-03-13 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function. ClinVar contains an entry for this variant (Variation ID: 845368). This variant is also known as p.Phe64Leu. A different variant (c.250T>C) giving rise to the same protein effect has been determined to be pathogenic (PMID: 2046936, 8721565, 28635949). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the TTR protein (p.Phe84Leu).
Molecular Genetics Laboratory, London Health Sciences Centre RCV001173295 SCV001336379 likely pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001048418 SCV001623421 pathogenic Amyloidogenic transthyretin amyloidosis 2021-05-10 criteria provided, single submitter clinical testing Variant summary: TTR c.252T>G (p.Phe84Leu) results in a non-conservative amino acid change located in the Transthyretin/hydroxyisourate hydrolase domain (IPR023416) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes (gnomAD). c.252T>G has been reported (also as Phe64Leu) in the literature in multiple individuals affected with Transthyretin Amyloidosis (example: Berk_2013, Iorio_2017, Rapezzi_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Other missense variants affecting the same codon and nearby residues (example: c.244G>A p.E82K, c.250T>A p.F84I, c.250T>G p.F84V, c.251T>C p.F84S) have been reported in the Human Gene Mutation Database in association with Amyloidosis suggesting this area might be mutational hotspot. Based on the evidence outlined above, the variant was classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.