Submissions for variant NM_000371.4(TTR):c.244G>A (p.Glu82Lys)

dbSNP: rs1555631402

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587406	SCV000696620	likely pathogenic	Amyloidosis, hereditary systemic 1	2019-09-11	criteria provided, single submitter	clinical testing	TTR c.244G>A (p.Glu82Lys) results in a conservative amino acid change in the Transthyretin/hydroxyisourate hydrolase domain (IPR023416). Three of five in-silico tools predict a benign effect of the variant. The variant is absent in 246222 control chromosomes. It has been reported in individuals affected with Transthyretin Amyloidosis (Briani_2012, Kufova_2018, Adams_2015, Jamet_2015) and has been observed in one patient with a clinical diagnosis of TTR cardiac amyloidosis as confirmed by physical findings, ECHO, technetium pyrophosphate scan and undergoing treatment by Tafamidis (personal communication). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating a functional impact has been reported. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined, the variant was re-classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000587406	SCV001376682	pathogenic	Amyloidosis, hereditary systemic 1	2020-06-10	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 29455155, 31718691, 25828388, 26208957, Invitae). This variant is also known as Glu62Lys and Glu61Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 495841). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 82 of the TTR protein (p.Glu82Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.
Ambry Genetics	RCV002456283	SCV002736805	likely pathogenic	Cardiovascular phenotype	2021-11-29	criteria provided, single submitter	clinical testing	The p.E82K variant (also known as c.244G>A), located in coding exon 3 of the TTR gene, results from a G to A substitution at nucleotide position 244. The glutamic acid at codon 82 is replaced by lysine, an amino acid with similar properties. This alteration, which is also referenced to as p.E62K, has been reported in individuals with transthyretin (TTR) amyloidosis and related cardiomyopathy (Adams D et al. Neurology, 2015 Aug;85:675-82; Jamet MP et al. Am. J. Surg. Pathol., 2015 Mar;:[ePub ahead of print]; Chyra Kufova Z et al. J Clin Pathol, 2018 Aug;71:687-694; (Damy T et al. Eur Heart J, 2019 Apr;:[ePub ahead of print]; Luigetti M et al. Brain Sci, 2020 Oct;10:[ePub ahead of print]; Salvalaggio A et al. J Neurol, 2021 Jan;268:189-198). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV000587406	SCV001749583	not provided	Amyloidosis, hereditary systemic 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 06-10-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.