rs267607159

chr18-31598616-G-Achr18-31598616-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BS2

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

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]

LOC124904277 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 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 id is 626843.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.385G>A	p.Ala129Thr	missense_variant	4/4	ENST00000237014.8
LOC124904277	XR_007066326.1	n.129-2921C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.385G>A	p.Ala129Thr	missense_variant	4/4	1	NM_000371.4	P1
TTR	ENST00000649620.1	c.385G>A	p.Ala129Thr	missense_variant	6/6			P1
TTR	ENST00000610404.5	c.289G>A	p.Ala97Thr	missense_variant	4/4	5

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

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251430 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135896

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

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: 0.000214 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

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 17, 2017	The p.Ala129Thr variant (rs267607159; also reported as p.Ala109Thr) has been shown to dominantly co-segregate in two families with euthyroid hyperthyroxinemia (Moses 1990 and Alves 1999); a clinically benign condition where levels of total serum thyroxine (T4) are elevated, but free T4 is normal and affected individuals do not have elevated levels of thyroid-stimulating hormone (TSH) or develop other signs of thyroid disease (Saraiva 2001). The mechanism behind these biochemical findings is thought to arise from increased binding affinity between T4 and serum TTR protein (one of three major protein carriers of T4) caused by particular amino acid substitutions in TTR. The p.Ala129Thr variant is one of a small number of such variants shown to result in increased binding affinity with T4 (Moses 1990) and is associated with euthyroid hyperthyroxinemia; including one other variant affecting the same codon, p.Ala129Val (Saraiva 2001 and GeneReviews). Pathogenic variants in TTR are associated with transthyretin-related hereditary amyloidosis (MIM: 105210); a variably presenting, multisystem disorder characterized by peripheral neuropathy with cardiomyopathy, and certain alleles in TTR are common causes of heart failure (Dungu 2016). The p.Ala129Thr variant has been identified in one individual included in a cohort of cardiomyopathy patients, although no additional clinical or genetic details were provided (Walsh 2017). This variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.006% (identified in 17 out of 277,164 chromosomes) and is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 43454). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2016	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 29, 2022	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2017	Variant summary: The TTR c.385G>A (p.Ala129Thr) variant involves the alteration of a conserved nucleotide and is predicted to be benign by 2/3 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 17/277164 control chromosomes (gnomAD), predominantly observed in the Latino subpopulation at a frequency of 0.000232 (8/34420). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic TTR variant (0.0000313), suggesting this is possibly a benign polymorphism found primarily in the populations of Latino origin. In vitro studies found that the mutant protein had an increased affinity for thyroxine (Moses 1990, Alves 1997), and an other study found a slightly decreased conformational stability for the variant monomers (Altland 2007). The variant has been reported to co-segregate with euthyroid hyperthyroxinemia (Moses 1990, Alves 1997, Sklate 2014), in agreement with the increased affinity for thyroxine. 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). Multiple clinical diagnostic laboratories classified this variant as uncertain significance. Taken together, though this variant is likely to be associated with euthyroid hyperthyroxinemia, it is classified as a VUS for hereditary amyloidosis and cardiomyopathy, until additional evidence becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 06, 2021	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. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 01, 2022

- -

Hyperthyroxinemia, dystransthyretinemic;C2751492:Familial amyloid neuropathy;C5779776:Carpal tunnel syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 10, 2022

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

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. -

Familial amyloid neuropathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

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

Affects, no assertion criteria provided

literature only

OMIM

Sep 01, 1996

- -

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
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	0.67	N
PrimateAI	Benign	0.46	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

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