ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.250T>C (p.Phe84Leu) (rs121918091)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236623 SCV000292703 pathogenic not provided 2015-03-25 criteria provided, single submitter clinical testing The F84L missense mutation in the TTR gene has been reported previously using alternative nomenclature (F64L) in a patient with amyloid-positive biopsies and transthyretin-related amyloidosis (Ii et al., 1991). A different nucleotide substitution (c.252 T>G) resulting in the same amino acid substitution (F84L) has also been reported in association with transthyretin-related amyloidosis (Rapezzi et al., 2013). Additionally, other amino acid substitutions at this same position (F84I and F84S) and many nearby missense mutations (T80A, E81K, E81G, G87E, I88L, Y89H) have been published is association with amyloidosis polyneuropathy (Stenson et al., 2013). Therefore, the presence of F84L is consistent with a diagnosis of transthyretin amyloidosis
Invitae RCV000014395 SCV000648565 pathogenic Amyloidogenic transthyretin amyloidosis 2019-12-27 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, 23279339, 22745357). This variant is also described as p.Phe64Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 13453). 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.
Integrated Genetics/Laboratory Corporation of America RCV000014395 SCV000696621 pathogenic Amyloidogenic transthyretin amyloidosis 2016-05-13 criteria provided, single submitter clinical testing Variant summary: The TTR c.250T>C (p.Phe84Leu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 121202 control chromosomes. The variant has been reported in numerous affected individuals in the literature and has been classified as pathogenic by a reputable database. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000236623 SCV000884819 pathogenic not provided 2017-10-24 criteria provided, single submitter clinical testing The TTR c.250T>C; p.Phe84Leu variant (also known as Phe64Leu) is published in the medical literature in individuals and families with transthyretin-related amyloidosis (Ii 1991, Rapezzi 2013, Russo 2012). The variant is listed in the ClinVar database (Variation ID: 13453), in the dbSNP variant database (rs121918091), and in the Genome Aggregation Database in 1/246212 alleles. The amino acid at this position is conserved across species and other amino acid substitutions at this codon are reported in individuals with transthyretin-related amyloidosis (Benson 2007, Rapezzi 2013, Uemichi 1999). Considering available information, this variant is classified as pathogenic. References: Benson MD et al. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007 Oct;36(4):411-23. Ii S et al. Two-tiered DNA-based diagnosis of transthyretin amyloidosis reveals two novel point mutations. Neurology. 1991 Jun;41(6):893-8. Rapezzi C et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013 Feb;34(7):520-8. Russo M et al. Transthyretin-related familial amyloidotic polyneuropathy: description of a cohort of patients with Leu64 mutation and late onset. J Peripher Nerv Syst. 2012 Dec;17(4):385-90. Uemichi T et al. Oculoleptomeningeal amyloidosis associated with a new transthyretin variant Ser64. Arch Neurol. 1999 Sep;56(9):1152-5.
Fulgent Genetics,Fulgent Genetics RCV000763027 SCV000893494 pathogenic Carpal tunnel syndrome; Dystransthyretinemic euthyroidal hyperthyroxinemia; Amyloidogenic transthyretin amyloidosis 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000236623 SCV001245841 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
OMIM RCV000014395 SCV000034644 pathogenic Amyloidogenic transthyretin amyloidosis 1996-01-01 no assertion criteria provided literature only

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