ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.206C>G (p.Thr69Ser) (rs1555631387)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000647353 SCV000769144 likely pathogenic Amyloidogenic transthyretin amyloidosis 2017-10-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 69 of the TTR protein (p.Thr69Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hereditary amyloidosis (PMID: 25044787, 26115788, Invitae). This variant is also known as p.Thr49Ser in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C55"). A different missense substitution at this codon (p.Thr69Ala) has been determined to be pathogenic (PMID: 1301926, 17503405, 20209591, 23713495, 21692911, 27859927). This suggests that the threonine residue is critical for TTR protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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