ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.262A>T (p.Ile88Leu) (rs121918085)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000014388 SCV000823548 pathogenic Amyloidogenic transthyretin amyloidosis 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 88 of the TTR protein (p.Ile88Leu). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs121918085, ExAC 0.01%). This variant has been observed to segregate with transthyretin amyloidosis in at least one family and has been reported in multiple individuals affected with this condition (PMID: 22745357, 1786038, 26537620, 26428663). ClinVar contains an entry for this variant (Variation ID: 13446). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; 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. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000014388 SCV000967004 likely pathogenic Amyloidogenic transthyretin amyloidosis 2019-03-08 criteria provided, single submitter clinical testing The p.Ile88Leu variant in TTR (also described as p.Ile68Leu in the literature) h as been identified in >20 individuals with clinical features of hereditary trans thyretin amyloidosis (ATTR; Almeida 1991, Hesse 1993, Salvi 2003, Perfetto 2011, Ihse 2013, Rapezzi 2013, Damy 2016, Iorio 2017) and segregated with disease in at least 5 individuals from at least one family (Rapezzi 2013). Clinical feature s in affected individuals included a mostly cardiac amyloidosis phenotype, with some neurologic and mixed cardiac/neurologic phenotypes. This variant has also b een reported by another clinical laboratory in ClinVar (Variation ID 13446) and has been identified in 5/129164 of European chromosomes by gnomAD (http://gnomad .broadinstitute.org). Results from an in vitro functional study using electropho retic analyses to assess the role of this variant show that while variant p.Ile8 8Leu TTR monomer could be clearly distinguished from its wild type counterpart, it did not result in a reduced conformational stability of both TTR monomers and tetramers (Altland 2007). The clinical significance of these results are uncert ain. Additionally, 7 mammals (squirrel, antelope, cow, goat, sheep, Tasmanian de vil, opossum) carry a Leucine (Leu) at this position with moderate nearby amino acid conservation and additional computational tools suggest that this variant m ay not impact the protein, though this information is not predictive enough to r ule out pathogenicity. In summary, although additional studies are required to f ully establish its clinical significance, this variant meets criteria to be clas sified as likely pathogenic for autosomal dominant ATTR based upon presence in m ultiple affected individuals and segregation studies. ACMG/AMP criteria applied: PS4, PP1_Moderate, BP4.
OMIM RCV000014388 SCV000034637 pathogenic Amyloidogenic transthyretin amyloidosis 1993-08-01 no assertion criteria provided literature only

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