ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.221A>G (p.Glu74Gly)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000371.4(TTR):c.221A>G (p.Glu74Gly)
Variation ID: 811803 Accession: VCV000811803.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31595140 (GRCh38) [ NCBI UCSC ] 18: 29175103 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 10, 2020 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.221A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Glu74Gly missense NC_000018.10:g.31595140A>G NC_000018.9:g.29175103A>G NG_009490.1:g.8374A>G LRG_416:g.8374A>G LRG_416t1:c.221A>G - Protein change
- E74G
- Other names
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- Canonical SPDI
- NC_000018.10:31595139:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TTR | - | - |
GRCh38 GRCh37 |
369 | 413 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Oct 17, 2018 | RCV001002179.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 18, 2019 | RCV001288933.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 13, 2022 | RCV002416289.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV003514451.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Oct 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160047.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The TTR c.221A>G; p.Glu74Gly variant, also known as Glu54Gly in the mature protein, is reported in the literature in multiple individuals affected with familial amyloid … (more)
The TTR c.221A>G; p.Glu74Gly variant, also known as Glu54Gly in the mature protein, is reported in the literature in multiple individuals affected with familial amyloid polyneuropathy (Durmus-Tekce 2016, Fontana 2015, Kim 2005, Pathak-Ray 2002, Reilly 1995, Saraiva 1995, Schanzer 2014). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 74 is highly conserved, and is located within a region of the protein that is a hotspot for amyloidogenic variants (Saraiva 1995), but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Additionally, other amino acid substitutions at this codon (Asp, Gln, Lys) have been reported in individuals with familial amyloid polyneuropathy (Eriksson 2009, Togashi 1999, Torres-Courchoud 2017). Based on available information, the p.Glu74Gly variant is considered to be likely pathogenic. References: Durmus-Tekce H et al. Genotypic and phenotypic presentation of transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey. Neuromuscul Disord. 2016 Jul;26(7):441-6. Eriksson M et al. Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with ATTR amyloid. Am J Surg Pathol. 2009 Jan;33(1):58-65. Fontana M et al.cDifferential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. Radiology. 2015 Nov;277(2):388-97. Kim HS et al. An aggressive form of familial amyloid polyneuropathy caused by a Glu54Gly mutation in the transthyretin gene. Eur J Neurol. 2005 Aug;12(8):657-9. Pathak-Ray V et al. Vitreous amyloidosis and secondary glaucoma-a case report. Eye (Lond). 2002 Jul;16(4):492-4. Reilly MM et al. Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy. Brain. 1995 Aug;118 ( Pt 4):849-56. Saraiva MJ et al. Transthyretin mutations in health and disease. Hum Mutat. 1995;5(3):191-6. Schanzer A et al. A woman with a rare p.Glu74Gly transthyretin mutation presenting exclusively with a rapidly progressive neuropathy: a case report. J Med Case Rep. 2014 Dec 4;8:403. Togashi S et al. An aggressive familial amyloidotic polyneuropathy caused by a new variant transthyretin Lys 54. Neurology. 1999 Aug 11;53(3):637-9. Torres-Courchoud I et al. Cardiac Involvement Secondary to a Familial Form of Transthyretin Amyloidosis Resulting From the Glu54Gln Mutation. Rev Esp Cardiol (Engl Ed). 2017 Apr;70(4):297-299. (less)
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Likely pathogenic
(Oct 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001476391.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. Found in multiple individuals … (more)
Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. Found in multiple individuals with expected phenotype for this gene. (less)
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Pathogenic
(Jun 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002724830.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.E74G pathogenic mutation (also known as c.221A>G), located in coding exon 3 of the TTR gene, results from an A to G substitution at … (more)
The p.E74G pathogenic mutation (also known as c.221A>G), located in coding exon 3 of the TTR gene, results from an A to G substitution at nucleotide position 221. The glutamic acid at codon 74 is replaced by glycine, an amino acid with similar properties. This alteration, which is also known as p.E54G, has been reported in numerous individuals with transthyretin (TTR) amyloidosis and related cardiomyopathy (Saraiva MJ. Hum Mutat, 1995;5:191-6; Pathak-Ray V et al. Eye (Lond), 2002 Jul;16:492-4; O'Hearn TM et al. Br J Ophthalmol, 2007 Dec;91:1607-9; Vrana JA et al. Haematologica, 2014 Jul;99:1239-47; Schänzer A et al. J Med Case Rep, 2014 Dec;8:403; Treibel TA et al. J Cardiovasc Comput Tomogr 2015 Jul;9:585-92; Durmu-Tekçe H et al. Neuromuscul Disord, 2016 07;26:441-6; Reynolds MM et al. Am J Ophthalmol, 2017 Nov;183:156-162; Muchtar E et al. J Neurol Sci, 2017 Aug;379:192-197; Choi K et al. J Clin Neurol, 2018 Oct;14:537-541; Lovley A et al. J Patient Rep Outcomes, 2021 Jan;5:3). Another alteration at the same codon, p.E74Q (c.220G>C), has been reported in two individuals with TTR amyloidosis (Rowczenio DM et al. Hum. Mutat., 2014 Sep;35:E2403-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004297826.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 74 of the TTR protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 74 of the TTR protein (p.Glu74Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TTR-related conditions (PMID: 7655883, 12101461, 16053476, 17522146, 25471118, 25997029, 26209459, 27238058, 28911993, 30198232, 33739616; Invitae). This variant is also known as Glu54Gly, E54G, Gly54. ClinVar contains an entry for this variant (Variation ID: 811803). 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.Glu74 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28911993; Invitae). 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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study. | Du K | Annals of clinical and translational neurology | 2021 | PMID: 33739616 |
Patient-reported burden of hereditary transthyretin amyloidosis on functioning and well-being. | Lovley A | Journal of patient-reported outcomes | 2021 | PMID: 33411323 |
Characteristics of South Korean Patients with Hereditary Transthyretin Amyloidosis. | Choi K | Journal of clinical neurology (Seoul, Korea) | 2018 | PMID: 30198232 |
Ocular Manifestations of Familial Transthyretin Amyloidosis. | Reynolds MM | American journal of ophthalmology | 2017 | PMID: 28911993 |
Acquired transthyretin amyloidosis after domino liver transplant: Phenotypic correlation, implication of liver retransplantation. | Muchtar E | Journal of the neurological sciences | 2017 | PMID: 28716239 |
Genotypic and phenotypic presentation of transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey. | Durmuş-Tekçe H | Neuromuscular disorders : NMD | 2016 | PMID: 27238058 |
Extracellular volume quantification by dynamic equilibrium cardiac computed tomography in cardiac amyloidosis. | Treibel TA | Journal of cardiovascular computed tomography | 2015 | PMID: 26209459 |
Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. | Fontana M | Radiology | 2015 | PMID: 25997029 |
Frequencies and geographic distributions of genetic mutations in transthyretin- and non-transthyretin-related familial amyloidosis. | Zhen DB | Clinical genetics | 2015 | PMID: 25211232 |
A woman with a rare p.Glu74Gly transthyretin mutation presenting exclusively with a rapidly progressive neuropathy: a case report. | Schänzer A | Journal of medical case reports | 2014 | PMID: 25471118 |
Clinical diagnosis and typing of systemic amyloidosis in subcutaneous fat aspirates by mass spectrometry-based proteomics. | Vrana JA | Haematologica | 2014 | PMID: 24747948 |
Role of the glutamic acid 54 residue in transthyretin stability and thyroxine binding. | Miyata M | Biochemistry | 2010 | PMID: 19950966 |
Early onset vitreous amyloidosis in familial amyloidotic polyneuropathy with a transthyretin Glu54Gly mutation is associated with elevated vitreous VEGF. | O'Hearn TM | The British journal of ophthalmology | 2007 | PMID: 17522146 |
An aggressive form of familial amyloid polyneuropathy caused by a Glu54Gly mutation in the transthyretin gene. | Kim HS | European journal of neurology | 2005 | PMID: 16053476 |
Vitreous amyloidosis and secondary glaucoma-a case report. | Pathak-Ray V | Eye (London, England) | 2002 | PMID: 12101461 |
Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy. | Reilly MM | Brain : a journal of neurology | 1995 | PMID: 7655883 |
Transthyretin mutations in health and disease. | Saraiva MJ | Human mutation | 1995 | PMID: 7599630 |
Thyroxine binding by human transthyretin variants: mutations at position 119, but not position 54, increase thyroxine binding affinity. | Curtis AJ | The Journal of clinical endocrinology and metabolism | 1994 | PMID: 7906282 |
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Text-mined citations for rs1598845097 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.