rs1555631402

Positions:

• chr18-31595163-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The ENST00000237014.8(TTR):​c.244G>A​(p.Glu82Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E82D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR ENST00000237014.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 3.64

Genes affected

TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000237014.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 18-31595163-G-A is Pathogenic according to our data. Variant chr18-31595163-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.244G>A	p.Glu82Lys	missense_variant	3/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.244G>A	p.Glu82Lys	missense_variant	3/4	1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000649620.1	c.244G>A	p.Glu82Lys	missense_variant	5/6			ENSP00000497927	P1
TTR	ENST00000610404.5	c.148G>A	p.Glu50Lys	missense_variant	3/4	5		ENSP00000477599
TTR	ENST00000541025.2	n.270G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2019	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. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 10, 2020	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). 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. 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. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	.;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.9	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	.;N;.;.
REVEL	Uncertain	0.56
Sift	Benign	0.12	.;T;.;.
Sift4G	Benign	0.20	.;T;T;D
Polyphen		0.046	B;B;.;.
Vest4		0.38, 0.42, 0.26
MutPred		0.68		Gain of methylation at E82 (P = 0.0122);Gain of methylation at E82 (P = 0.0122);Gain of methylation at E82 (P = 0.0122);Gain of methylation at E82 (P = 0.0122);
MVP		0.99
MPC		0.54
ClinPred		0.73	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555631402; hg19: chr18-29175126;