NM_000371.4(TTR):c.239C>T (p.Thr80Ile) AND Amyloidosis, hereditary systemic 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 4, 2025
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:: RCV000700173.23

Allele description [Variation Report for NM_000371.4(TTR):c.239C>T (p.Thr80Ile)]

NM_000371.4(TTR):c.239C>T (p.Thr80Ile)

Gene:

TTR:transthyretin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_000371.4(TTR):c.239C>T (p.Thr80Ile)

HGVS:

NC_000018.10:g.31595158C>T
NG_009490.1:g.8392C>T
NM_000371.4:c.239C>TMANE SELECT
NP_000362.1:p.Thr80Ile
NP_000362.1:p.Thr80Ile
LRG_416t1:c.239C>T
LRG_416:g.8392C>T
LRG_416p1:p.Thr80Ile
NC_000018.9:g.29175121C>T
NM_000371.3:c.239C>T

Protein change:

T80I

Links:

dbSNP: rs1254341785

NCBI 1000 Genomes Browser:

rs1254341785

Molecular consequence:

NM_000371.4:c.239C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Amyloidosis, hereditary systemic 1 (AMYLD1)
Synonyms:: Amyloidosis Transthyretin related; Amyloid polyneuropathy transthyretin related; Hereditary oculoleptomeningeal amyloid angiopathy; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0971004; MedGen: C2751492; Orphanet: 85447; Orphanet: 85451; OMIM: 105210

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000828918	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 3722385, 12050338, 15820680, 21992998, 25997029, 26017327, 28492532
SCV004808023	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 4, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005044765	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000828918

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 20, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004808023

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 4, 2025)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005044765

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis.

Wallace MR, Dwulet FE, Conneally PM, Benson MD.

J Clin Invest. 1986 Jul;78(1):6-12.

PubMed [citation]

PMID:: 3722385
PMCID:: PMC329523

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

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000828918.7

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

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 80 of the TTR protein (p.Thr80Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (Invitae). ClinVar contains an entry for this variant (Variation ID: 577420). 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.Thr80 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 3722385, 12050338, 15820680, 21992998, 25997029, 26017327). 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.

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004808023.2

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV005044765.2

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

Description

The missense c.239C>Tp.Thr80Ile variant in TTR gene has been reported in heterozygous state in individuals affected withtransthyretin amyloidosis Abouelhoda M, et. al., 2021; Chaudhary AG, et. al., 2022. The p.Thr80Ile variant is novel not in anyindividuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likelypathogenic multiple submissions. The amino acid change p.Thr80Ile in TTR is predicted as conserved by GERP++ and PhyloPacross 100 vertebrates. The amino acid Thr at position 80 is changed to a Ile changing protein sequence and it might alter itscomposition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic.

#	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

Last Updated: Jan 13, 2025

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