NM_000371.4:c.385G>A

Variant names:

• chr18-31598616-G-A
• rs267607159
• NM_000371.4:c.385G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM5 PP2 BS2_Supporting

The NM_000371.4(TTR):​c.385G>A​(p.Ala129Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000502 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A129S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9 O:1
• Conservation: PhyloP100: 3.61
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• amyloidosis, hereditary systemic 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• familial amyloid neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary ATTR amyloidosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• heart conduction disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• ATTRV122I amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294516 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000371.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31598616-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 626843.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 108 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0149 (below the threshold of 3.09). Trascript score misZ: 1.5458 (below the threshold of 3.09). GenCC associations: The gene is linked to familial amyloid neuropathy, amyloidosis, hereditary systemic 1, ATTRV122I amyloidosis, hereditary ATTR amyloidosis, heart conduction disease.
• BS2: High AC in GnomAd4 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 rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.385G>A	p.Ala129Thr	missense_variant	Exon 4 of 4	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-2921C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.385G>A	p.Ala129Thr	missense_variant	Exon 4 of 4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.385G>A	p.Ala129Thr	missense_variant	Exon 6 of 6			ENSP00000497927.1
TTR	ENST00000610404.5	c.289G>A	p.Ala97Thr	missense_variant	Exon 4 of 4	5		ENSP00000477599.2
ENSG00000294516	ENST00000724044.1	n.286-2921C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251430 AF XY: 0.0000442

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000513 AC: 75 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42 AN XY: 727222

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74438

African (AFR) AF: 0.0000722 AC: 3 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Apr 29, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A129T variant of uncertain significance in the TTR gene (also reported as A109T due to alternate nomenclature) has been reported to co-segregate with disease in two unrelated families with euthyroid hyperthyroxinemia (Moses et al., 1990; Alves et al., 1997). However, in both families, no clinical symptoms related to familial amyloidosis were observed (Moses et al., 1990; Alves et al., 1997). Another clinical laboratory has observed A129T in one individual with HCM who also harbored a pathogenic variant in the MYBPC3 gene (Landrum et al., 2014). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense variants in the same residue (A129S, A129V) have been reported in association with hereditary amyloidosis and euthyroid hyperthyroxinemia, respectively (Date et al., 1997; Refetoff et al., 1996). In addition, missense variants in nearby residues (I127F, I127V, I127M, L131M) have been reported in the Human Gene Mutation Database in association with hereditary amyloidosis (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Functional studies show that A129T results in increased affinity of thyroxine to the TTR protein (Moses et al., 1990; Alves et al., 1997). The A129T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position where amino acids with similar properties to Alanine are tolerated across species, although T129 is tolerated in at least one species. Nevertheless, in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TTR c.385G>A; p.Ala129Thr variant (rs267607159), also known as Ala109Thr in traditional nomenclature, is reported in the literature in two families with euthyroid hyperthyroxinemia (Alves 1999, Moses 1990). This variant is also reported in an individual from a cardiomyopathy cohort, but without clear disease association (Walsh 2017). This variant is also reported in ClinVar (Variation ID: 43454), and is found in the general population with an overall allele frequency of 0.0060% (17/282814 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.559). Functional analyses of the variant protein show increased binding affinity with T4 (Moses 1990), consistent with the euthyroid hyperthyroxinemia association. Other in vitro functional analyses demonstrate amyloid levels similar to wild type, suggesting the variant may not have an increased potential to form amyloid fibrils (Grether 2022). Based on the available information, the p.Ala129Thr variant is associated with clinically benign euthyroid hyperthyroxinemia, but its association with cardiomyopathy cannot be determined with certainty. References: Alves et al. Screening and biochemical characterization of transthyretin variants in the Portuguese population. Hum Mutat. 1997; 9(3): 226-233. PMID: 9090525. Grether NB et al. Amyloidogenicity assessment of transthyretin gene variants. Ann Clin Transl Neurol. 2022 Aug;9(8):1252-1263. PMID: 35903975. Moses et al. A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia. J Clin Invest. 1990; 86(6): 2025-2033. PMID: 1979335. Walsh et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017; 19(2): 192-203. PMID: 27532257. -

not specified Uncertain:2

Apr 06, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala129Thr variant in TTR has been reported in one individual with hypertrophic cardiomyopathy who also carried a pathogenic MYBPC3 variant and in several individuals from one family with euthyroid hyperthyroxinemia but no symptoms of transthyretin amyloidosis (Moses 1990 PMID: 1979335, Walsh 2017 PMID: 27532257, LMM data). It has also been identified in 0.02% (8/35440) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant leads to an increased affinity of thyroxine (T4) to the TTR protein (Moses 1990 PMID: 1979335, Alves 1997 PMID: 9090525); however, these types of assays may not accurately represent biological function and computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Additional variants involving this codon (p.Ala129Ser and p.Ala129Val) have been identified; p.Ala129Ser in individuals with hereditary amyloidosis (Date 1997 PMID: 9268242), and p.Ala129Val in individuals with euthyroid hyperthyroxinemia (Refetoff 1996 PMID: 8784093). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting. -

Mar 31, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTR c.385G>A (p.Ala129Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251430 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTR causing Transthyretin Amyloidosis phenotype (3.1e-05). c.385G>A has been reported in the literature in individuals affected with Transthyretin Amyloidosis and this variant co-segregated with euthyroid hyperthyroxinemia (Moses_1990, Alves_1997, Sklate_2014, Abouelhoda_2021). The variant was also found in a patient with hypertrophic cardiomyopathy (HCM), though without strong evidence for causality (Walsh 2017). In addition, a clinical laboratory that a HCM patient carrying this variant also carried a pathogenic MYBPC3 variant (LMM-PH unpublished data). In vitro studies found that the mutant protein had an increased affinity for thyroxine (Moses 1990, Alves 1997), and another study found a slightly decreased conformational stability for the variant monomers (Altland 2007). The following publications have been ascertained in the context of this evaluation (PMID: 34380564, 17503405, 9090525, 1979335, 27532257). ClinVar contains an entry for this variant (Variation ID: 43454). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiomyopathy Uncertain:1

Feb 01, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Apr 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A129T variant (also known as c.385G>A and A109T), located in coding exon 4 of the TTR gene, results from a G to A substitution at nucleotide position 385. The alanine at codon 129 is replaced by threonine, an amino acid with similar properties. This alteration (also referred to as A109T) has been reported to segregate with euthyroid hyperthyroxinemia in two families; however, none had any symptoms of transthyretin amyloidosis (Moses AC et al. J. Clin. Invest. 1990;86:2025-33; Alves IL et al. Hum Mutat. 1997;9(3):226-33). This variant has also been detected in one individual with hypertrophic cardiomyopathy, but clinical details were limited (Walsh R et al. Genet. Med. 2017;19:192-203). Functional studies indicate that this variant increases the affinity of TTR for T4, but suggest it may not be associated with increased potential to form amyloid fibrils (Moses AC et al. J. Clin. Invest. 1990;86:2025-33; Alves IL et al. Hum Mutat. 1997;9(3):226-33; Rosen HN et al. Endocrinology. 1994;134:27-34; Grether NB et al. Ann Clin Transl Neurol. 2022 Aug;9(8):1252-1263). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration with respect to amyloidosis and cardiac indications remains unclear. -

Amyloidosis, hereditary systemic 1 Uncertain:1

Jan 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 129 of the TTR protein (p.Ala129Thr). This variant is present in population databases (rs267607159, gnomAD 0.02%). This missense change has been observed in individual(s) with euthyroid hyperthyroxinemia and/or hypertrophic cardiomyopathy (PMID: 1979335, 27532257). This variant is also known as p.Ala109Thr. ClinVar contains an entry for this variant (Variation ID: 43454). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TTR function (PMID: 1979335). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hyperthyroxinemia, dystransthyretinemic Other:1

Sep 01, 1996

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;D;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.87	.;D;T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.4	L;L;.
PhyloP100		3.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.87	.;N;.
REVEL	Uncertain	0.56
Sift	Benign	0.19	.;T;.
Sift4G	Benign	0.31	.;T;T
Polyphen		0.63	P;P;.
Vest4		0.38, 0.49
MVP		1.0
MPC		0.58
ClinPred		0.10	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.92
Mutation Taster		=12/88	disease causing

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

Other links and lift over

dbSNP: rs267607159; hg19: chr18-29178579; COSMIC: COSV52701391; COSMIC: COSV52701391;