ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.238A>G (p.Thr80Ala) (rs121918070)

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Total submissions: 11
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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 RCV000014363 SCV000053246 pathogenic Amyloidogenic transthyretin amyloidosis 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000014363 SCV000060026 pathogenic Amyloidogenic transthyretin amyloidosis 2021-04-06 criteria provided, single submitter clinical testing The p.Thr80Ala variant (also described as p.Thr60Ala in the literature) in TTR has been reported in >80 individuals with hereditary transthyretin amyloidosis (ATTR), many of which had cardiac involvement and segregated with disease in 7 affected individuals from 5 families (Wallace 1986 PMID: 3722385, Benson 1987 PMID: 3030336, Koeppen 1990 PMID: 2122246, Reilly 1995 PMID: 7608709, Kotani 2002 PMID: 12000195, Lachmann 2002 PMID: 12050338, Graham 2012, Sattianayagam 2012 PMID: 21992998, Fontana 2015 PMID: 25997029, Lanoue 2016 PMID: 26959691, Auer-Grumbach 2020 PMID: 32674397, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 13421) and has been identified in 0.001% (1/113738) of European chromosomes by gnomAD ( In vitro functional studies provide some evidence that this variant impacts protein function (Altland 2007 PMID: 17503405). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary transthyretin amyloidosis. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Supporting.
GeneDx RCV000159427 SCV000209373 pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing The T80A pathogenic variant in the TTR gene (also known as T60A due to a difference in cDNA numbering) has been reported in populations around the world in association with hereditary amyloidosis, amyloidotic cardiomyopathy, and polyneuropathy (Wallace et al., 1986; Benson et al., 1987; Saunton et al., 1991; Kotani et al., 2002; Lachmann et al., 2002; Connors et al., 2011; Sattianayagam et al., 2012; Arruda-Olso et al., 2013; Ihse et al., 2013; Swiecicki et al., 2015). Swiecicki et al. (2015) identified T80A in 58 patients with a clinical diagnosis of TTR amyloidosis; all of the patients had histological evidence of amyloid deposition, two had a cardiac transplant, and ten had a liver transplant. The mean age at diagnosis was 64 years-old and the variant was associated with decreased survival (Swiecicki et al., 2015). This variant has also been identified in several unrelated individuals who were referred for cardiomyopathy genetic testing at GeneDx. This variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). Moreover, functional studies demonstrated that T80A induces conformational changes within the TTR monomers which result in the destablization of the native structure of these monomers compared to wildtype, leading to amyloidogenic potential (Altland et al., 2007; Cendron et al., 2009).In summary, the T80A variant in the TTR gene is interpreted as a pathogenic variant which is associated with autosomal dominant, late-onset TTR amyloidosis.
Invitae RCV000014363 SCV000541954 pathogenic Amyloidogenic transthyretin amyloidosis 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 80 of the TTR protein (p.Thr80Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with amyloidosis in several families (PMID: 7608709). This variant has been observed in multiple individuals affected with amyloidosis (PMID: 21992998, 26017327, 25997029, 3722385, 12050338). This variant is also known as p.Thr60Ala in the literature. ClinVar contains an entry for this variant (Variation ID: 13421). This variant has been reported to affect TTR protein function (PMID: 15820680). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000159427 SCV000616213 pathogenic not provided 2019-09-26 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852477 SCV000995171 pathogenic Cardiomyopathy 2018-12-24 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002097 SCV001159944 pathogenic none provided 2020-04-07 criteria provided, single submitter clinical testing The TTR c.238A>G; p.Thr80Ala variant (rs121918070), also known as p.Thr60Ala, is reported in the literature in multiple individuals and families affected with hereditary amyloidosis, associated mainly with amyloidotic cardiomyopathy and a poor prognosis (Altland 2007, Dohrn 2013, Fontana 2015, Ihse 2013, Lachmann 2002, Pilebro 2016, Swiecicki 2015, Waits 1995, Wallace 1986). This variant is the most common pathogenic TTR variant in the United Kingdom, and has high prevalence in northwest Ireland (Reilly 1995, Sattianayagam 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13421), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 80 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, functional analyses of the variant protein show a reduction in stability compared to the wild-type protein (Cendron 2009, Sekijima 2005). Based on available information, the p.Thr80Ala variant is considered to be pathogenic. References: Altland K et al. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. Cendron L et al. Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses. J Biol Chem. 2009 Sep 18;284(38):25832-41. Dohrn MF et al. Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy. J Neurol. 2013 Dec;260(12):3093-108. Fontana M et al. Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. Radiology. 2015 Nov;277(2):388-97. Ihse E et al. Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. Amyloid. 2013 Sep;20(3):142-50. Lachmann HJ et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002 Jun 6;346(23):1786-91. Pilebro B et al. (99m)Tc-DPD uptake reflects amyloid fibril composition in hereditary transthyretin amyloidosis. Ups J Med Sci. 2016;121(1):17-24. Reilly MM et al. Familial amyloid polyneuropathy (TTR ala 60) in north west Ireland: a clinical, genetic, and epidemiological study. J Neurol Neurosurg Psychiatry. 1995 Jul;59(1):45-9. Sattianayagam PT et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J. 2012 May;33(9):1120-7. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. Swiecicki PL et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-31. Waits RP et al. Low plasma concentrations of retinol-binding protein in individuals with mutations affecting position 84 of the transthyretin molecule. Clin Chem. 1995 Sep;41(9):1288-91. Wallace MR et al. Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis. J Clin Invest. 1986 Jul;78(1):6-12.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173293 SCV001336377 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
OMIM RCV000014363 SCV000034612 pathogenic Amyloidogenic transthyretin amyloidosis 2002-06-06 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000159427 SCV000280535 likely pathogenic not provided 2014-02-20 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Thr60Ala variant (aka p.Thr80Ala). This variant has been reported in many cases of amyloidosis. It has been associated with carpel tunnel syndrome, cardiac amyloidosis, and polyneuropathy.
GenomeConnect, ClinGen RCV000014363 SCV001423371 not provided Amyloidogenic transthyretin amyloidosis no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 11-13-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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