NM_000371.4(TTR):c.238A>G (p.Thr80Ala) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: May 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000159427.28

Allele description [Variation Report for NM_000371.4(TTR):c.238A>G (p.Thr80Ala)]

NM_000371.4(TTR):c.238A>G (p.Thr80Ala)

Gene:

TTR:transthyretin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_000371.4(TTR):c.238A>G (p.Thr80Ala)

Other names:

T60A; p.T80A:ACT>GCT

HGVS:

NC_000018.10:g.31595157A>G
NG_009490.1:g.8391A>G
NM_000371.4:c.238A>GMANE SELECT
NP_000362.1:p.Thr80Ala
NP_000362.1:p.Thr80Ala
LRG_416t1:c.238A>G
LRG_416:g.8391A>G
LRG_416p1:p.Thr80Ala
NC_000018.9:g.29175120A>G
NM_000371.3:c.238A>G
P02766:p.Thr80Ala
c.238A>G
p.THR80ALA

Protein change:

T80A; THR60ALA

Links:

UniProtKB: P02766#VAR_007573; OMIM: 176300.0004; dbSNP: rs121918070

NCBI 1000 Genomes Browser:

rs121918070

Molecular consequence:

NM_000371.4:c.238A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000209373	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 7, 2020)	germline	clinical testing	Citation Link,
SCV000280535	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Likely pathogenic (Feb 20, 2014)	germline	clinical testing
SCV000616213	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Dec 7, 2022)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 12050338, 15217993, 15820680, 17503405, 19602727, 3722385, 7655883, 26017327, 21992998, 20660862, 7608709, 14968122, 14724437, 27033334, 23638696, 31139689, 25430583, 24101130, 26243339, 26467025
SCV001159944	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Feb 22, 2023)	germline	clinical testing	Citation Link,
SCV002021561	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 21, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005046488	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	7	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.

Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, Pepys MB, Hawkins PN.

N Engl J Med. 2002 Jun 6;346(23):1786-91.

PubMed [citation]

PMID:: 12050338

Identification of transthyretin variants by sequential proteomic and genomic analysis.

Bergen HR 3rd, Zeldenrust SR, Butz ML, Snow DS, Dyck PJ, Dyck PJ, Klein CJ, O'Brien JF, Thibodeau SN, Muddiman DC.

Clin Chem. 2004 Sep;50(9):1544-52. Epub 2004 Jun 24.

PubMed [citation]

PMID:: 15217993

See all PubMed Citations (21)

Details of each submission

From GeneDx, SCV000209373.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280535.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV000616213.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001159944.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002021561.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV005046488.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		7	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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