ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.112G>A (p.Asp38Asn) (rs1567945632)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000693117 SCV000820973 likely pathogenic Amyloidogenic transthyretin amyloidosis 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 38 of the TTR protein (p.Asp38Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with TTR-related amyloidosis (PMID: 23126592, Invitae). This variant is listed in a TTR mutation database (PMID: 14640030). This variant is also described as p.Asp18Asn 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 C15"). A different missense substitution at this codon (p.Asp38Gly, also known as p.Asp18Gly) has been determined to be pathogenic (PMID: 8579098, 15820680, 20209591, 17503405). This suggests that the aspartic acid residue is critical for TTR protein function and that other missense substitutions at this position may also be pathogenic. A second, different missense substitution at this codon (p.Asp38Glu, also known as p.Asp18Glu) has been reported in individuals affected with TTR-related amyloidosis (PMID: 25644864, 17503405, 23713495). 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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