ClinVar

Description

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.