ClinVar Miner

Submissions for variant NM_000371.3(TTR):c.128G>A (p.Ser43Asn) (rs1598844112)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000819070 SCV000959712 pathogenic Amyloidogenic transthyretin amyloidosis 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 43 of the TTR protein (p.Ser43Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. 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: 10439117, 22149423, 23713495, 26428663, 22400056, 28878402). This variant is also known as p.Ser23Asn. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Not Available; PolyPhen-2: Possibly Damaging; Align-GVGD: Not Available). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285076 SCV001471425 likely pathogenic none provided 2020-04-29 criteria provided, single submitter clinical testing The TTR c.128G>A; p.Ser43Asn variant, also known as Ser23Asn, is reported in the literature in multiple individuals affected with transthyretin-related amyloidosis (Castano 2012, Ihse 2013, Mueller 2010, Rapezzi 2013). This variant is reported in ClinVar (Variation ID: 661615), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Functional analyses demonstrate reduced monomer stability and positive for amyloid formation on endomyocardial biopsies from multiple patients (Castano 2012, Mueller 2010). The serine at codon 43 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Based on available information, this variant is considered to be likely pathogenic. References: Castano A et al. Technetium pyrophosphate myocardial uptake and peripheral neuropathy in a rare variant of familial transthyretin (TTR) amyloidosis (Ser23Asn): a case report and literature review. Amyloid. 2012;19(1):41–46. Ihse E et al. Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. Amyloid. 2013;20(3):142–150. Mueller II et al. Restrictive cardiomyopathy in inherited ATTR amyloidosis (TTR-Ser23Asn) in a patient of German-Italian extraction. BMJ Case Rep. 2010;2010:bcr06.2009.2032. Rapezzi C et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013;34(7):520–528.

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