rs121918070

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong

The NM_000371.4(TTR):c.238A>G(p.Thr80Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T80I) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 2.63

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000371.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-31595158-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 577420.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=3, Uncertain_significance=1}.

PP5

Variant 18-31595157-A-G is Pathogenic according to our data. Variant chr18-31595157-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595157-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4 linkuse as main transcript	c.238A>G	p.Thr80Ala	missense_variant	3/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TTR	ENST00000237014.8 linkuse as main transcript	c.238A>G	p.Thr80Ala	missense_variant	3/4	1	NM_000371.4	P1
TTR	ENST00000649620.1 linkuse as main transcript	c.238A>G	p.Thr80Ala	missense_variant	5/6			P1
TTR	ENST00000610404.5 linkuse as main transcript	c.142A>G	p.Thr48Ala	missense_variant	3/4	5
TTR	ENST00000541025.2 linkuse as main transcript	n.264A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251442

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727238

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:

0.0000162

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2022	This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls, therefore the frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In some published literature, this variant is referred to as p.Thr60Ala. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15820680, 17503405, 19602727) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	Common pathogenic variant in the TTR gene, which has been reported in populations around the world in association with hereditary amyloidosis, amyloidotic cardiomyopathy, and polyneuropathy, and is the most common TTR variant in the UK and North-West Ireland (Wallace et al., 1986; Benson et al., 1987; Koeppen et al., 1990; Saunton et al., 1991; Kotani et al., 2002; Lachmann et al., 2002; Connors et al., 2011; Sattianayagam et al., 2012; Arruda-Olso et al., 2013; Ihse et al., 2013; Swiecicki et al., 2015; Reilly 1995); Observed in 58 patients with a clinical diagnosis of TTR amyloidosis; all had histological evidence of amyloid deposition, two had a cardiac transplant, and ten had a liver transplant (Swiecicki et al., 2015); Reported to segregate with amyloidosis in several families (Wallace et al., 1986; Koeppen et al., 1990; Reilly et al., 1995); Also reported as T60A due to a difference in cDNA numbering; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Functional studies demonstrate this variant induces conformational changes within the TTR monomers that result in the destablization of the native structure of these monomers compared to wildtype, leading to amyloidogenic potential (Altland et al., 2007; Cendron et al., 2009); Reported in ClinVar as pathogenic (ClinVar Variant ID #13421; ClinVar); This variant is associated with the following publications: (PMID: 19602727, 26894299, 17968687, 24517438, 25604431, 1644839, 3722385, 21992998, 23713495, 12050338, 12000195, 24131106, 1664269, 3030336, 2122246, 15820680, 21838471, 22620962, 27033334, 26610878, 25997029, 24101130, 26959691, 26849806, 32674397, 26017327, 7608709, 26656838, 17503405) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 22, 2023	The TTR c.238A>G; p.Thr80Ala variant (rs121918070), also known as p.Thr60Ala, is reported in the literature in multiple individuals and families affected with hereditary amyloidosis, associated mainly with amyloidotic cardiomyopathy at a late age of onset and a poor prognosis (Altland 2007, Dohrn 2013, Fontana 2015, Ihse 2013, Lachmann 2002, Pilebro 2016, Swiecicki 2015, Waits 1995, Wallace 1986). This variant is the most common pathogenic TTR variant in the United Kingdom, and has high prevalence in northwest Ireland (Reilly 1995, Sattianayagam 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13421), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 80 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.675). However, functional analyses of the variant protein show a reduction in stability compared to the wild-type protein (Cendron 2009, Sekijima 2005). Based on available information, the p.Thr80Ala variant is considered to be pathogenic. References: Altland K et al. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. PMID: 17503405. Cendron L et al. Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses. J Biol Chem. 2009 Sep 18;284(38):25832-41. PMID: 19602727. Dohrn MF et al. Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy. J Neurol. 2013 Dec;260(12):3093-108. PMID: 24101130. Fontana M et al. Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. Radiology. 2015 Nov;277(2):388-97. PMID: 25997029. Ihse E et al. Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. Amyloid. 2013 Sep;20(3):142-50. PMID: 23713495. Lachmann HJ et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002 Jun 6;346(23):1786-91. PMID: 12050338. Pilebro B et al. (99m)Tc-DPD uptake reflects amyloid fibril composition in hereditary transthyretin amyloidosis. Ups J Med Sci. 2016;121(1):17-24. PMID: 26849806. Reilly MM et al. Familial amyloid polyneuropathy (TTR ala 60) in north west Ireland: a clinical, genetic, and epidemiological study. J Neurol Neurosurg Psychiatry. 1995 Jul;59(1):45-9. PMID: 7608709. Sattianayagam PT et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J. 2012 May;33(9):1120-7. PMID: 21992998. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. PMID: 15820680. Swiecicki PL et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-31. PMID: 26017327. Waits RP et al. Low plasma concentrations of retinol-binding protein in individuals with mutations affecting position 84 of the transthyretin molecule. Clin Chem. 1995 Sep;41(9):1288-91. PMID: 7656439. Wallace MR et al. Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis. J Clin Invest. 1986 Jul;78(1):6-12. PMID: 3722385. -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 20, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Thr60Ala variant (aka p.Thr80Ala). This variant has been reported in many cases of amyloidosis. It has been associated with carpel tunnel syndrome, cardiac amyloidosis, and polyneuropathy. -

Familial amyloid neuropathy

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 80 of the TTR protein (p.Thr80Ala). This variant is present in population databases (rs121918070, gnomAD 0.0009%). This missense change has been observed in individuals with amyloidosis (PMID: 3722385, 12050338, 21992998, 25997029, 26017327). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr60Ala. ClinVar contains an entry for this variant (Variation ID: 13421). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TTR protein function. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 06, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 11-13-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 27, 2023	The p.Thr80Ala variant (also described as p.Thr60Ala in the literature) in TTR has been reported in >80 individuals with hereditary transthyretin amyloidosis (ATTR), many of which had cardiac involvement, and segregated with disease in 7 affected relatives from 5 families (Wallace 1986 PMID: 3722385, Benson 1987 PMID: 3030336, Koeppen 1990 PMID: 2122246, Reilly 1995 PMID: 7608709, Kotani 2002 PMID: 12000195, Lachmann 2002 PMID: 12050338, Graham 2012, Sattianayagam 2012 PMID: 21992998, Fontana 2015 PMID: 25997029, Lanoue 2016 PMID: 26959691, Auer-Grumbach 2020 PMID: 32674397, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 13421) and has been identified in 0.003% (2/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant impacts protein function (Altland 2007 PMID: 17503405). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary transthyretin amyloidosis. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Supporting. -

Charcot-Marie-Tooth disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Dec 24, 2018

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The c.238A>G (p.T80A) alteration is located in exon 3 (coding exon 3) of the TTR gene. This alteration results from an A to G substitution at nucleotide position 238, causing the threonine (T) at amino acid position 80 to be replaced by an alanine (A). Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/251442) total alleles studied. The highest observed frequency was 0.001% (1/113738) of European (non-Finnish) alleles. This pathogenic mutation has been detected in multiple individuals with familial transthyretin amyloidosis and is associated with cardiac symptoms (Wallace, 1986; Zeldenrust, 2012; Ihse, 2013; Swiecicki, 2015). In one study of a cohort of 60 individuals with this mutation, 42% presented primarily with cardiac symptoms; autonomic and peripheral nerve dysfunction were observed in 42% and 23% of individuals, respectively (Sattianayagam, 2012). This amino acid position is highly conserved in available vertebrate species. In a functional study, the authors demonstrated that TTR monomers with this mutation are in an unfolded state 80% of the time in 2.5M urea (Altland, 2007). In addition, analysis of the crystallized structure showed that this mutation changes the conformation, suggesting that this mutation is destabilizing to the TTR protein structure (Cendron, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Pathogenic

0.84

D;D;T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.018

FATHMM_MKL

Benign

0.70

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.74

D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.8

L;L;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.45

Polyphen

0.15

B;B;.;.

Vest4

0.58, 0.65, 0.79

MutPred

0.69

Loss of phosphorylation at T80 (P = 0.0349);Loss of phosphorylation at T80 (P = 0.0349);Loss of phosphorylation at T80 (P = 0.0349);Loss of phosphorylation at T80 (P = 0.0349);

MVP

1.0

MPC

0.68

ClinPred

0.39

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.92

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