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

gnomAD frequency: 0.00001  dbSNP: rs121918070

Total submissions: 14

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	Familial amyloid neuropathy	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000014363	SCV000060026	pathogenic	Familial amyloid neuropathy	2023-06-27	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 relatives 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 0.003% (2/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). 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	2020-12-07	criteria provided, single submitter	clinical testing	Common pathogenic variant in the TTR gene, which has been reported in populations around the world in association with hereditary amyloidosis, amyloidotic cardiomyopathy, and polyneuropathy, and is the most common TTR variant in the UK and North-West Ireland (Wallace et al., 1986; Benson et al., 1987; Koeppen et al., 1990; 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; Reilly 1995); Observed in 58 patients with a clinical diagnosis of TTR amyloidosis; all had histological evidence of amyloid deposition, two had a cardiac transplant, and ten had a liver transplant (Swiecicki et al., 2015); Reported to segregate with amyloidosis in several families (Wallace et al., 1986; Koeppen et al., 1990; Reilly et al., 1995); Also reported as T60A due to a difference in cDNA numbering; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Functional studies demonstrate this variant induces conformational changes within the TTR monomers that 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); Reported in ClinVar as pathogenic (ClinVar Variant ID #13421; ClinVar); This variant is associated with the following publications: (PMID: 19602727, 26894299, 17968687, 24517438, 25604431, 1644839, 3722385, 21992998, 23713495, 12050338, 12000195, 24131106, 1664269, 3030336, 2122246, 15820680, 21838471, 22620962, 27033334, 26610878, 25997029, 24101130, 26959691, 26849806, 32674397, 26017327, 7608709, 26656838, 17503405)
Invitae	RCV000014363	SCV000541954	pathogenic	Familial amyloid neuropathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 80 of the TTR protein (p.Thr80Ala). This variant is present in population databases (rs121918070, gnomAD 0.0009%). This missense change has been observed in individuals with amyloidosis (PMID: 3722385, 12050338, 21992998, 25997029, 26017327). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr60Ala. ClinVar contains an entry for this variant (Variation ID: 13421). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TTR protein function. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000159427	SCV000616213	pathogenic	not provided	2022-12-07	criteria provided, single submitter	clinical testing	This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls, therefore the frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In some published literature, this variant is referred to as p.Thr60Ala. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15820680, 17503405, 19602727)
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	RCV000159427	SCV001159944	pathogenic	not provided	2023-02-22	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 at a late age of onset 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, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.675). 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. PMID: 17503405. 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. PMID: 19602727. Dohrn MF et al. Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy. J Neurol. 2013 Dec;260(12):3093-108. PMID: 24101130. 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. PMID: 25997029. 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. PMID: 23713495. Lachmann HJ et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002 Jun 6;346(23):1786-91. PMID: 12050338. 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. PMID: 26849806. 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. PMID: 7608709. 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. PMID: 21992998. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. PMID: 15820680. Swiecicki PL et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-31. PMID: 26017327. 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. PMID: 7656439. 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. PMID: 3722385.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173293	SCV001336377	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000159427	SCV002021561	likely pathogenic	not provided	2021-10-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453258	SCV002737088	pathogenic	Cardiovascular phenotype	2023-04-26	criteria provided, single submitter	clinical testing	The c.238A>G (p.T80A) alteration is located in exon 3 (coding exon 3) of the TTR gene. This alteration results from an A to G substitution at nucleotide position 238, causing the threonine (T) at amino acid position 80 to be replaced by an alanine (A). Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/251442) total alleles studied. The highest observed frequency was 0.001% (1/113738) of European (non-Finnish) alleles. This pathogenic mutation has been detected in multiple individuals with familial transthyretin amyloidosis and is associated with cardiac symptoms (Wallace, 1986; Zeldenrust, 2012; Ihse, 2013; Swiecicki, 2015). In one study of a cohort of 60 individuals with this mutation, 42% presented primarily with cardiac symptoms; autonomic and peripheral nerve dysfunction were observed in 42% and 23% of individuals, respectively (Sattianayagam, 2012). This amino acid position is highly conserved in available vertebrate species. In a functional study, the authors demonstrated that TTR monomers with this mutation are in an unfolded state 80% of the time in 2.5M urea (Altland, 2007). In addition, analysis of the crystallized structure showed that this mutation changes the conformation, suggesting that this mutation is destabilizing to the TTR protein structure (Cendron, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000159427	SCV005046488	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing
OMIM	RCV000014363	SCV000034612	pathogenic	Familial amyloid neuropathy	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	Familial amyloid neuropathy		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.