rs730881165

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM5PP5BP4BS2_Supporting

The NM_000371.4(TTR):c.301G>A(p.Ala101Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A101V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: -0.250

Variant links:

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]

TTR links:

TTR (HGNC:):

TTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a helix (size 6) in uniprot entity TTHY_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000371.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-31595221-C-T is described in Lovd as [Pathogenic].

PP5

Variant 18-31595220-G-A is Pathogenic according to our data. Variant chr18-31595220-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181696.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Pathogenic=1, Likely_pathogenic=2}. Variant chr18-31595220-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.3047328). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4 linkuse as main transcript	c.301G>A	p.Ala101Thr	missense_variant	3/4	ENST00000237014.8	NP_000362.1	P02766E9KL36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TTR	ENST00000237014.8 linkuse as main transcript	c.301G>A	p.Ala101Thr	missense_variant	3/4	1	NM_000371.4	ENSP00000237014.4	P02766
TTR	ENST00000649620.1 linkuse as main transcript	c.301G>A	p.Ala101Thr	missense_variant	5/6			ENSP00000497927.1	P02766
TTR	ENST00000610404.5 linkuse as main transcript	c.205G>A	p.Ala69Thr	missense_variant	3/4	5		ENSP00000477599.2	A0A087WT59
TTR	ENST00000541025.2 linkuse as main transcript	n.327G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251436

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000307

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 04, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 26, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2024	Variant summary: TTR c.301G>A (p.Ala101Thr) results in a non-conservative amino acid change located in the transthyretin/hydroxyisourate hydrolase domain (IPR023416) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251436 control chromosomes. c.301G>A has been reported in the literature in individuals affected with Transthyretin Amyloidosis, however often with limited evidence for causality (i.e. lack of segregation data or family history) (e.g. Benson_2003, Connors_2003, Obici_2012, Quarta_2014, Sperry_2018, Damy_2019, Bampatsias_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15123043, 14640030, 30938420, 15645642, 22551192, 24563469, 17338921, 30336828, 37805173). ClinVar contains an entry for this variant (Variation ID: 181696). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2019	Reported in a patient with a TTR-related cardiac phenotype in the published literature (Connors et al., 2003); reported as Ala81Thr due to the use of alternate nomenclature; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 181696; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17338921, 15123043, 22551192, 14640030, 15645642) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 02, 2024	PP2, PP4, PM2_moderate, PS4_moderate -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

The c.301G>A (p.A101T) alteration is located in exon 3 (coding exon 3) of the TTR gene. This alteration results from a G to A substitution at nucleotide position 301, causing the alanine (A) at amino acid position 101 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/251436) total alleles studied. The highest observed frequency was 0.006% (1/16256) of African/African American alleles. This variant was reported in multiple individuals with features consistent with hereditary transthyretin-related amyloidosis; including one proband with immunohistochemically-confirmed diagnosis of hereditary transthyretin-related amyloidosis (Connors, 2003; Obici, 2012; Quarta, 2014; Sperry, 2018; external communication). This amino acid position is poorly conserved in available vertebrate species. Based on internal structural assessment, this alteration leads to destabilization of the native form of TTR that is similar to other established pathogenic variants in the vicinity (Wojtczak, 2001; Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Amyloidosis, hereditary systemic 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 101 of the TTR protein (p.Ala101Thr). This variant is present in population databases (rs730881165, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of TTR-related conditions (PMID: 21520333; Invitae). ClinVar contains an entry for this variant (Variation ID: 181696). 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 with a positive predictive value of 95%. This variant disrupts the p.Ala101 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

0.14

DANN

Benign

0.52

DEOGEN2

Uncertain

0.77

D;D;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.67

.;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.30

T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.7

L;L;.;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.71

.;N;.;.

REVEL

Uncertain

0.56

Sift

Benign

0.27

.;T;.;.

Sift4G

Benign

0.58

.;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.22, 0.39, 0.73

MutPred

0.60

Gain of ubiquitination at K96 (P = 0.1222);Gain of ubiquitination at K96 (P = 0.1222);Gain of ubiquitination at K96 (P = 0.1222);Gain of ubiquitination at K96 (P = 0.1222);

MVP

0.87

MPC

0.46

ClinPred

0.052

GERP RS

-4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over