18-31593020-C-T

Variant names:

• chr18-31593020-C-T
• rs730881169
• NM_000371.4:c.194C>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.194C>T​(p.Ala65Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. A65D) 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: 3.33

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 16 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 chr18-31593020-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 18-31593020-C-T is Pathogenic according to our data. Variant chr18-31593020-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.194C>T	p.Ala65Val	missense_variant	Exon 2 of 4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.194C>T	p.Ala65Val	missense_variant	Exon 2 of 4	1	NM_000371.4	ENSP00000237014.4

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

Feb 06, 2025

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. This variant has been identified in at least one individual with clinical features associated with this gene. In some published literature, this variant is referred to as p.Ala45Val. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. -

Cardiovascular phenotype Pathogenic:1

Apr 23, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A65V variant (also known as c.194C>T and p.A45V), located in coding exon 2 of the TTR gene, results from a C to T substitution at nucleotide position 194. The alanine at codon 65 is replaced by valine, an amino acid with similar properties. This alteration has been identified in one individual with hereditary transthyretin amyloidosis (hATTR) (Adams D et al. Neurology, 2015 Aug;85:675-82). 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.A65T, 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; Pilebro B et al. Ups. J. Med. Sci. 2016 Feb;121:17-24). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Amyloidosis, hereditary systemic 1 Pathogenic:1

Aug 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as A45V. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala65 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 1570831, 24953234, 28460244), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 448841). This missense change has been observed in individual(s) with TTR-related conditions (PMID: 26208957, 35933469). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 65 of the TTR protein (p.Ala65Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	.;D;.;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0060	.;D;.;.
Sift4G	Benign	0.078	.;T;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.66, 0.71, 0.74
MutPred		0.63		Loss of disorder (P = 0.0583);Loss of disorder (P = 0.0583);Loss of disorder (P = 0.0583);Loss of disorder (P = 0.0583);
MVP		1.0
MPC		1.3
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.97

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: rs730881169; hg19: chr18-29172983; COSMIC: COSV52701904;