rs121918078

Positions:

• chr18-31593019-G-A
• chr18-31593019-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000371.4(TTR):​c.193G>A​(p.Ala65Thr) 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. A65S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.69

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 16 ACMG points.

• PM1: In a strand (size 7) in uniprot entity TTHY_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 18-31593019-G-A is Pathogenic according to our data. Variant chr18-31593019-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 850453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31593019-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.193G>A	p.Ala65Thr	missense_variant	2/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.193G>A	p.Ala65Thr	missense_variant	2/4	1	NM_000371.4	ENSP00000237014	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 15, 2019

Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2022

The p.A65T pathogenic mutation (also known as c.193G>A), located in coding exon 2 of the TTR gene, results from a G to A substitution at nucleotide position 193. The alanine at codon 65 is replaced by threonine, an amino acid with similar properties. This alteration has been reported (often with nomenclature p.A45T) in individuals with hereditary transthyretin amyloidosis (hATTR) (Saraiva MJ et al. Am. J. Hum. Genet., 1992 May;50:1027-30; Cortese A et al. J. Neurol., 2016 May;263:916-924; Chao HC et al. Ann Clin Transl Neurol, 2019 May;6:913-922). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Zanotti G et al. Eur. J. Biochem., 1995 Dec;234:563-9; Ambry internal data). Other alterations impacting the same codon (p.A65V, p.A65G, p.A65S, and p.A65D) have also been described in association with hATTR (Saraiva MJ et al. Am. J. Hum. Genet. 1992 May;50:1027-30; Janunger T et al. Amyloid. 2000 Jun;7(2):137-40; Adams D et al. Neurology, 2015 Aug;85:675-82; Pilebro B et al. Ups. J. Med. Sci. 2016 Feb;121:17-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Amyloidosis, hereditary systemic 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 05, 2019

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala65 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7599630, 23713495, 24953234, 28460244, 10842718). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). This variant has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1570831, 31139689). This variant is also known as Ala45Thr in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 65 of the TTR protein (p.Ala65Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.83	.;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.3	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	.;N;.;.
REVEL	Pathogenic	0.70
Sift	Benign	0.19	.;T;.;.
Sift4G	Benign	0.20	.;T;T;T
Polyphen		0.95	P;P;.;.
Vest4		0.68, 0.73, 0.85
MutPred		0.74		Gain of phosphorylation at A65 (P = 0.0285);Gain of phosphorylation at A65 (P = 0.0285);Gain of phosphorylation at A65 (P = 0.0285);Gain of phosphorylation at A65 (P = 0.0285);
MVP		1.0
MPC		1.2
ClinPred		0.93	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.96

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: rs121918078; hg19: chr18-29172982;