rs1555631393

Positions:

• chr18-31595139-G-A
• chr18-31595139-G-C
• chr18-31595139-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000237014.8(TTR):​c.220G>A​(p.Glu74Lys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E74Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR ENST00000237014.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.80

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 18 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000237014.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31595140-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 811803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 18-31595139-G-A is Pathogenic according to our data. Variant chr18-31595139-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 636837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595139-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.220G>A	p.Glu74Lys	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.220G>A	p.Glu74Lys	missense_variant	3/4	1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000649620.1	c.220G>A	p.Glu74Lys	missense_variant	5/6			ENSP00000497927	P1
TTR	ENST00000610404.5	c.124G>A	p.Glu42Lys	missense_variant	3/4	5		ENSP00000477599
TTR	ENST00000541025.2	n.246G>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

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 30, 2018

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2019

The p.E74K pathogenic mutation (also known as c.220G>A and E54K), located in coding exon 3 of the TTR gene, results from a G to A substitution at nucleotide position 220. The glutamic acid at codon 74 is replaced by lysine, an amino acid with similar properties. This mutation was identified in multiple individuals diagnosed with TTR amyloidosis or familial amyloid polyneuropathy (Togashi S et al. Neurology, 1999 Aug;53:637-9; Ihse E et al. Amyloid, 2013 Sep;20:142-50; Veronese C et al. Amyloid, 2013 Dec;20:269-71; Koike H et al. J. Neurol. Sci., 2018 11;394:99-106) and was shown to segregate with disease in 3 families (Busse A et al. Am. J. Med. Genet. A, 2004 Jul;128A:190-4; Rapezzi C et al. Eur. Heart J., 2013 Feb;34:520-8; Bekircan-Kurt CE et al. Neuromuscul. Disord., 2015 Sep;25:686-92). In addition, another disease-causing mutation, p.E74Q, has been described in the same codon (Rowczenio DM et al. Hum. Mutat., 2014 Sep;35:E2403-12). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Amyloidosis, hereditary systemic 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	.;N;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.016	.;D;.;.
Sift4G	Uncertain	0.040	.;D;D;D
Polyphen		0.99	D;D;.;.
Vest4		0.82, 0.82, 0.89
MutPred		0.79		Gain of ubiquitination at E74 (P = 0.0114);Gain of ubiquitination at E74 (P = 0.0114);Gain of ubiquitination at E74 (P = 0.0114);Gain of ubiquitination at E74 (P = 0.0114);
MVP		1.0
MPC		1.4
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.99

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: rs1555631393; hg19: chr18-29175102;