ClinVar Genomic variation as it relates to human health

Variant summary: Variant affects a conserved nucleotide and results in a replacement of a large size and aromatic (Y) with a medium size and polar Histidine (H). 4/4 in silico tools predict the variant to be disease causing. It is absent from the large and broad cohorts of the ExAC project while it was reported in several ATTR patients. Patients presented with a wide range of symptoms including oculoleptomeningeal amyloidosis, seizures and steadily progressing dementia with amyloid deposit findings at autopsy indicating pathogenicity. One database classifies variant as pathogenic. Considering all evidence, the variant was classified as Pathogenic.

The TTR c.265T>C;p.Tyr89His variant (rs121918100), also known as Tyr69His in alternative nomenclature, has been published in individuals with oculoleptomenmingeal amyloidosis or ataxia and dementia and been demonstrated to segregate with disease in at least one family (Blevins 2003, Schweitzer 2009, Ziskin 2015). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at amino acid 89 is highly conserved, and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Functional studies further suggest the variant protein has decreased thermodynamic stability and slow tetramer dissociation (Sekijima 2005), although it is not clear that these properties contribute to pathogenesis. Considering available information, the p.Tyr89His variant is considered to be likely pathogenic. References: Blevins G et al. Oculoleptomeningeal amyloidosis in a large kindred with a new transthyretin variant Tyr69His. Neurology. 2003 May 27;60(10):1625-30. Schweitzer K et al. Oculoleptomeningeal amyloidosis in 3 individuals with the transthyretin variant Tyr69His. Can J Ophthalmol. 2009 Jun;44(3):317-9. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. Ziskin JL et al. Neuropathologic analysis of Tyr69His TTR variant meningovascular amyloidosis with dementia. Acta Neuropathol Commun. 2015 Jul 10;3:43.

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect TTR protein function (PMID: 15820680). This variant has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 19491989, 19922332, 26156087, 31257920, 31718691). This variant is also known as Y69H or Tyr69His in the literature. ClinVar contains an entry for this variant (Variation ID: 13466). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 89 of the TTR protein (p.Tyr89His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine.

The p.Y89H variant (also known as c.265T>C), located in coding exon 3 of the TTR gene, results from a T to C substitution at nucleotide position 265. The tyrosine at codon 89 is replaced by histidine, an amino acid with similar properties. This alteration has been detected in multiple individuals with transthyretin (TTR) amyloidosis, primarily TTR leptomeningeal/central nervous system amyloidosis (Schweitzer K et al. Can J Ophthalmol, 2009 Jun;44:317-9; Suhr OB et al. Amyloid, 2009 Dec;16:208-14; Ziskin JL et al. Acta Neuropathol Commun, 2015 Jul;3:43; Yamada Y et al. Amyloid, 2019 Dec;26:251-252; He S et al. Orphanet J Rare Dis, 2019 11;14:251). Experimental studies show that this alteration may impact protein function (Sekijima Y et al. Cell, 2005 Apr;121:73-85).This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.