Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001002179 | SCV001160047 | likely pathogenic | not specified | 2018-10-17 | criteria provided, single submitter | clinical testing | The TTR c.221A>G; p.Glu74Gly variant, also known as Glu54Gly in the mature protein, is reported in the literature in multiple individuals affected with familial amyloid polyneuropathy (Durmus-Tekce 2016, Fontana 2015, Kim 2005, Pathak-Ray 2002, Reilly 1995, Saraiva 1995, Schanzer 2014). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 74 is highly conserved, and is located within a region of the protein that is a hotspot for amyloidogenic variants (Saraiva 1995), but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Additionally, other amino acid substitutions at this codon (Asp, Gln, Lys) have been reported in individuals with familial amyloid polyneuropathy (Eriksson 2009, Togashi 1999, Torres-Courchoud 2017). Based on available information, the p.Glu74Gly variant is considered to be likely pathogenic. References: Durmus-Tekce H et al. Genotypic and phenotypic presentation of transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey. Neuromuscul Disord. 2016 Jul;26(7):441-6. Eriksson M et al. Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with ATTR amyloid. Am J Surg Pathol. 2009 Jan;33(1):58-65. Fontana M et al.cDifferential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. Radiology. 2015 Nov;277(2):388-97. Kim HS et al. An aggressive form of familial amyloid polyneuropathy caused by a Glu54Gly mutation in the transthyretin gene. Eur J Neurol. 2005 Aug;12(8):657-9. Pathak-Ray V et al. Vitreous amyloidosis and secondary glaucoma-a case report. Eye (Lond). 2002 Jul;16(4):492-4. Reilly MM et al. Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy. Brain. 1995 Aug;118 ( Pt 4):849-56. Saraiva MJ et al. Transthyretin mutations in health and disease. Hum Mutat. 1995;5(3):191-6. Schanzer A et al. A woman with a rare p.Glu74Gly transthyretin mutation presenting exclusively with a rapidly progressive neuropathy: a case report. J Med Case Rep. 2014 Dec 4;8:403. Togashi S et al. An aggressive familial amyloidotic polyneuropathy caused by a new variant transthyretin Lys 54. Neurology. 1999 Aug 11;53(3):637-9. Torres-Courchoud I et al. Cardiac Involvement Secondary to a Familial Form of Transthyretin Amyloidosis Resulting From the Glu54Gln Mutation. Rev Esp Cardiol (Engl Ed). 2017 Apr;70(4):297-299. |
| Athena Diagnostics | RCV001288933 | SCV001476391 | likely pathogenic | not provided | 2019-10-18 | criteria provided, single submitter | clinical testing | Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. Found in multiple individuals with expected phenotype for this gene. |
| Ambry Genetics | RCV002416289 | SCV002724830 | pathogenic | Cardiovascular phenotype | 2022-06-13 | criteria provided, single submitter | clinical testing | The p.E74G pathogenic mutation (also known as c.221A>G), located in coding exon 3 of the TTR gene, results from an A to G substitution at nucleotide position 221. The glutamic acid at codon 74 is replaced by glycine, an amino acid with similar properties. This alteration, which is also known as p.E54G, has been reported in numerous individuals with transthyretin (TTR) amyloidosis and related cardiomyopathy (Saraiva MJ. Hum Mutat, 1995;5:191-6; Pathak-Ray V et al. Eye (Lond), 2002 Jul;16:492-4; O'Hearn TM et al. Br J Ophthalmol, 2007 Dec;91:1607-9; Vrana JA et al. Haematologica, 2014 Jul;99:1239-47; Schänzer A et al. J Med Case Rep, 2014 Dec;8:403; Treibel TA et al. J Cardiovasc Comput Tomogr 2015 Jul;9:585-92; Durmu-Tekçe H et al. Neuromuscul Disord, 2016 07;26:441-6; Reynolds MM et al. Am J Ophthalmol, 2017 Nov;183:156-162; Muchtar E et al. J Neurol Sci, 2017 Aug;379:192-197; Choi K et al. J Clin Neurol, 2018 Oct;14:537-541; Lovley A et al. J Patient Rep Outcomes, 2021 Jan;5:3). Another alteration at the same codon, p.E74Q (c.220G>C), has been reported in two individuals with TTR amyloidosis (Rowczenio DM et al. Hum. Mutat., 2014 Sep;35:E2403-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV003514451 | SCV004297826 | pathogenic | Amyloidosis, hereditary systemic 1 | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 74 of the TTR protein (p.Glu74Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TTR-related conditions (PMID: 7655883, 12101461, 16053476, 17522146, 25471118, 25997029, 26209459, 27238058, 28911993, 30198232, 33739616; Invitae). This variant is also known as Glu54Gly, E54G, Gly54. ClinVar contains an entry for this variant (Variation ID: 811803). 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) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 95%. This variant disrupts the p.Glu74 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28911993; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |