ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.265T>C (p.Tyr89His) (rs121918100)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586493 SCV000696622 pathogenic Amyloidogenic transthyretin amyloidosis 2016-04-15 criteria provided, single submitter clinical testing 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756861 SCV000884818 likely pathogenic none provided 2019-12-26 criteria provided, single submitter clinical testing 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.
Mendelics RCV000586493 SCV001140871 pathogenic Amyloidogenic transthyretin amyloidosis 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000586493 SCV001586490 pathogenic Amyloidogenic transthyretin amyloidosis 2020-06-28 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). 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 has been reported to affect TTR protein function (PMID: 15820680). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014408 SCV000034657 pathogenic AMYLOIDOSIS, LEPTOMENINGEAL, TRANSTHYRETIN-RELATED 2003-05-27 no assertion criteria provided literature only

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