NM_000371.4(TTR):c.325G>C (p.Glu109Gln) AND Amyloidosis, hereditary systemic 1

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 3, 2024
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:: RCV000014384.29

Allele description [Variation Report for NM_000371.4(TTR):c.325G>C (p.Glu109Gln)]

NM_000371.4(TTR):c.325G>C (p.Glu109Gln)

Gene:

TTR:transthyretin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_000371.4(TTR):c.325G>C (p.Glu109Gln)

Other names:

E89Q

HGVS:

NC_000018.10:g.31595244G>C
NG_009490.1:g.8478G>C
NM_000371.4:c.325G>CMANE SELECT
NP_000362.1:p.Glu109Gln
NP_000362.1:p.Glu109Gln
LRG_416t1:c.325G>C
LRG_416:g.8478G>C
LRG_416p1:p.Glu109Gln
NC_000018.9:g.29175207G>C
NM_000371.3:c.325G>C
P02766:p.Glu109Gln

Protein change:

E109Q; GLU89GLN

Links:

UniProtKB: P02766#VAR_007585; OMIM: 176300.0026; dbSNP: rs121918082

NCBI 1000 Genomes Browser:

rs121918082

Molecular consequence:

NM_000371.4:c.325G>C - 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
SCV000034633	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1992)	germline	literature only	PubMed (1) [See all records that cite this PMID] Salvi, F., Ferlini, A., Plasmati, R., Rubboli, G., Michelucci, R., Forti, A., Saraiva, M. J. M., Costa, P. P., Altland, K., Tassinari, C. A. Familial amyloidotic polyneuropathy in Italy. Arquivos Med. 3: 19-24, 1990.,
SCV000696627	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 13, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9748569, 24767411, 22747647, 24073013, 16530227, 15110620, 27858761, 27238058 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001392545	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 3, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1301926, 28635949, 10842705, 20209591, 25644864, 28911993, 28492532
SCV002754560	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	no assertion criteria provided (ACMG Guidelines, 2015)	Likely pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A simple screening test for variant transthyretins associated with familial transthyretin amyloidosis using isoelectric focusing.

Connors LH, Ericsson T, Skare J, Jones LA, Lewis WD, Skinner M.

Biochim Biophys Acta. 1998 Sep 30;1407(3):185-92.

PubMed [citation]

PMID:: 9748569

THAOS: gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease.

Wixner J, Mundayat R, Karayal ON, Anan I, Karling P, Suhr OB; THAOS investigators.

Orphanet J Rare Dis. 2014 Apr 27;9:61. doi: 10.1186/1750-1172-9-61.

PubMed [citation]

PMID:: 24767411
PMCID:: PMC4005902

See all PubMed Citations (16)

Details of each submission

From OMIM, SCV000034633.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a Sicilian family, Almeida et al. (1992) identified a glu89-to-gln substitution in transthyretin (E89Q) as the basis of amyloidosis presenting as neuropathy and cardiomyopathy (AMYLD1; 105210). In this and another Sicilian family (see 176300.0025), the TTR variants had been detected by isoelectric focusing (IEF); one was a neutral TTR variant and the other (E89Q) was basic. Three patients in the family with the E89Q mutation presented with carpal tunnel syndrome as the initial manifestation. Many years later, it was followed by polyneuropathy and cardiomyopathy responsible in 1 patient for intractable heart failure and death (Salvi et al., 1990).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696627.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: The TTR c.325G>C (p.Glu109Gln) variant involves the alteration of a conserved nucleotide, resulting in a missense change within the transthyretin/hydroxyisourate hydrolase domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent from the large control database ExAC (0/121328 control chromosomes). The variant has been identified in numerous heterozygous patients and families with transthyretin amyloidosis (e.g., Wixner_OJRD_2014; Nardo_TP_2004; Durmus-Tekce_Neuromusc Dis_2016). Overlapping and nearby disease-associated mutations such as E109K, H108R, H110N and H110D suggest the residue and the motif are critical for proper protein function. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001392545.6

#	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 glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 109 of the TTR protein (p.Glu109Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) and hATTR amyloidosis (PMID: 1301926, 28635949). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Glu89Gln (E89Q). ClinVar contains an entry for this variant (Variation ID: 13442). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 95%. This variant disrupts the p.Glu109 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10842705, 20209591, 25644864, 28911993). 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 Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV002754560.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 22, 2025

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