18-31595125-C-T

Variant names:

• chr18-31595125-C-T
• NM_000371.4:c.206C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000371.4(TTR):​c.206C>T​(p.Thr69Ile) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T69A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.33

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.

• PS1: Transcript NM_000371.4 (TTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a chain Transthyretin (size 126) in uniprot entity TTHY_HUMAN there are 141 pathogenic changes around while only 6 benign (96%) 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 chr18-31595124-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 18-31595125-C-T is Pathogenic according to our data. Variant chr18-31595125-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1454801.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-31595125-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.206C>T	p.Thr69Ile	missense_variant	Exon 3 of 4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.206C>T	p.Thr69Ile	missense_variant	Exon 3 of 4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.206C>T	p.Thr69Ile	missense_variant	Exon 5 of 6			ENSP00000497927.1
TTR	ENST00000610404.5	c.110C>T	p.Thr37Ile	missense_variant	Exon 3 of 4	5		ENSP00000477599.2
TTR	ENST00000541025.2	n.232C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

TTR-related disorder Pathogenic:1

Mar 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TTR c.206C>T variant is predicted to result in the amino acid substitution p.Thr69Ile. This variant is alternatively referred to as p.Thr49Ile using legacy nomenclature. This variant has been reported in multiple individuals with transthyretin-related amyloidosis with variable expressivity and patients presenting with both neurologic and/or cardiac features (Ando et al. 2013. PubMed ID: 23425518; Nakamura et al. 1999. PubMed ID: 10436378; Suhr et al. 2016. PubMed ID: 26656838; Skrahina et al. 2021. PubMed ID: 34658264). This variant has not been reported in a large population database, indicating it is rare in the general population. Alternative nucleotide substitutions affecting the same amino acid (p.Thr69Pro, p.Thr69Ala, and p.Thr69Ser), have been reported in multiple individuals with transthyretin-related amyloidosis (Suhr et al. 2016. PubMed ID: 26656838; Iorio et al. 2017. PubMed ID: 28635949; Ikura et al. 2022. PubMed ID: 35149236). This variant is interpreted as pathogenic. -

Amyloidosis, hereditary systemic 1 Pathogenic:1

Dec 19, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine with isoleucine at codon 69 of the TTR protein (p.Thr69Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of hereditary transthyretin amyloidosis (PMID: 10436378, 17503405, 26537620). This variant is also known as p.Thr49Ile. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function. This variant disrupts the p.Thr69 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301926, 17503405, 20209591, 23713495, 21692911, 27859927). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.5	.;D;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	.;D;.;.
Sift4G	Pathogenic	0.0010	.;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.96, 0.96, 0.95
MutPred		0.91		Loss of phosphorylation at T69 (P = 0.0409);Loss of phosphorylation at T69 (P = 0.0409);Loss of phosphorylation at T69 (P = 0.0409);Loss of phosphorylation at T69 (P = 0.0409);
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-29175088;