ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.173A>C (p.Asp58Ala)
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.173A>C (p.Asp58Ala)
Variation ID: 644083 Accession: VCV000644083.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31592999 (GRCh38) [ NCBI UCSC ] 18: 29172962 (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 Aug 14, 2019 Feb 14, 2024 Apr 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.173A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Asp58Ala missense NC_000018.10:g.31592999A>C NC_000018.9:g.29172962A>C NG_009490.1:g.6233A>C LRG_416:g.6233A>C LRG_416t1:c.173A>C LRG_416p1:p.Asp58Ala - Protein change
- D58A
- Other names
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- Canonical SPDI
- NC_000018.10:31592998:A:C
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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
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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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 22, 2023 | RCV000797923.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 6, 2018 | RCV002406755.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 30, 2022 | RCV003117589.3 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058192.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 25644864, 23346293, PS4_S). A different missense change at the same codon has … (more)
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 25644864, 23346293, PS4_S). A different missense change at the same codon has been reported to be associated with TTR related disorder (PMID:24412190,12050338, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.654, 3CNET: 0.94, PP3_P). A missense variant is a common mechanism associated with Amyloidosis (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Constipation (present) , Hypertensive disorder (present) , Left ventricular hypertrophy (present)
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Pathogenic
(Sep 06, 2018)
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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: SCV002715758.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.D58A pathogenic mutation (also known as c.173A>C and D38A), located in coding exon 2 of the TTR gene, results from an A to C … (more)
The p.D58A pathogenic mutation (also known as c.173A>C and D38A), located in coding exon 2 of the TTR gene, results from an A to C substitution at nucleotide position 173. The aspartic acid at codon 58 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been reported in several individuals with amyloidosis with features including polyneuropathy, autonomic dysfunction, and cardiac involvement (Tachibana N et al. Amyloid. 1999;6:282-8; Yazaki M et al. Biochem Biophys Res Commun. 2000;274:702-6; Cho HJ et al. J Cardiovasc Ultrasound. 2012;20:209-12), and has been reported as a common cause of amyloidosis in Korean patients (Jang MA et al. Ann Hum Genet. 2015;79:99-107). In addition, other alterations affecting this codon (p.D58V and p.D58Y) have also been reported in association with disease (Lachmann HJ et al. N Engl J Med. 2002;346(23):1786-91; Fontana M et al. JACC Cardiovasc Imaging. 2014;7(2):157-65). 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
(Sep 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799317.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The TTR c.173A>C; p.Asp58Ala variant (rs1598844213), also known as Asp38Ala in the mature protein, is reported in the literature in several individuals affected with transthyretin-related … (more)
The TTR c.173A>C; p.Asp58Ala variant (rs1598844213), also known as Asp38Ala in the mature protein, is reported in the literature in several individuals affected with transthyretin-related amyloidosis (Cho 2012, Choi 2018, Jang 2015, Yazaki 2000), and is suggested to be a founder variant in the Korean population (Choi 2018). This variant is also reported in ClinVar (Variation ID: 644083), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.172G>T, p.Asp58Tyr; c.173A>T, p.Asp58Val) have been reported in individuals with transthyretin-related amyloidosis (Fontana 2014, He 2019, Lachmann 2002, Lavigne Moreira 2015, Lipowska 2020). The aspartate at codon 58 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.654). Based on available information, this variant is considered to be pathogenic. REFERENCES Cho HJ et al. Familial Transthyretin Amyloidosis with Variant Asp38Ala Presenting with Orthostatic Hypotension and Chronic Diarrhea. J Cardiovasc Ultrasound. 2012 Dec;20(4):209-12. PMID: 23346293. Choi K et al. Characteristics of South Korean Patients with Hereditary Transthyretin Amyloidosis. J Clin Neurol. 2018 Oct;14(4):537-541. PMID: 30198232. Fontana M et al. Native T1 mapping in transthyretin amyloidosis. JACC Cardiovasc Imaging. 2014 Feb;7(2):157-65. PMID: 24412190. He S et al. Clinical characteristics and prognosis of Chinese patients with hereditary transthyretin amyloid cardiomyopathy. Orphanet J Rare Dis. 2019 Nov 12;14(1):251. PMID: 31718691. Jang MA et al. Asp58Ala is the predominant mutation of the TTR gene in Korean patients with hereditary transthyretin-related amyloidosis. Ann Hum Genet. 2015 Mar;79(2):99-107. PMID: 25644864. 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. Lavigne Moreira et al. Transthyretin Asp38Tyr: a new mutation associated to a late onset neuropathy. J Peripher Nerv Syst. 2015 Mar;20(1):60-2. PMID: 25857202. Lipowska M et al. Transthyretin-related familial amyloid polyneuropathy (ATTR-FAP) in Poland - genetic and clinical presentation. Neurol Neurochir Pol. 2020;54(6):552-560. PMID: 33373035. Yazaki M et al. Cardiac amyloid in patients with familial amyloid polyneuropathy consists of abundant wild-type transthyretin. Biochem Biophys Res Commun. 2000 Aug 11;274(3):702-6. PMID: 10924339. (less)
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Pathogenic
(Apr 22, 2023)
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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: SCV000937510.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant is also known as Asp38Ala. This missense change has been observed in individual(s) with familial transthyretin amyloidosis (PMID: 10611949, 23346293, 25644864). This variant … (more)
This variant is also known as Asp38Ala. This missense change has been observed in individual(s) with familial transthyretin amyloidosis (PMID: 10611949, 23346293, 25644864). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 58 of the TTR protein (p.Asp58Ala). ClinVar contains an entry for this variant (Variation ID: 644083). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp58 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 12050338, 24412190, 25857202), which suggests that this may be a clinically significant amino acid residue. 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. (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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Transthyretin Asp38Tyr: a new mutation associated to a late onset neuropathy. | Lavigne Moreira C | Journal of the peripheral nervous system : JPNS | 2015 | PMID: 25857202 |
Asp58Ala is the predominant mutation of the TTR gene in Korean patients with hereditary transthyretin-related amyloidosis. | Jang MA | Annals of human genetics | 2015 | PMID: 25644864 |
Native T1 mapping in transthyretin amyloidosis. | Fontana M | JACC. Cardiovascular imaging | 2014 | PMID: 24412190 |
Familial Transthyretin Amyloidosis with Variant Asp38Ala Presenting with Orthostatic Hypotension and Chronic Diarrhea. | Cho HJ | Journal of cardiovascular ultrasound | 2012 | PMID: 23346293 |
Biochemical characteristics of variant transthyretins causing hereditary leptomeningeal amyloidosis. | Mitsuhashi S | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2005 | PMID: 16399646 |
Tabulation of human transthyretin (TTR) variants, 2003. | Connors LH | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2003 | PMID: 14640030 |
Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. | Lachmann HJ | The New England journal of medicine | 2002 | PMID: 12050338 |
Cardiac amyloid in patients with familial amyloid polyneuropathy consists of abundant wild-type transthyretin. | Yazaki M | Biochemical and biophysical research communications | 2000 | PMID: 10924339 |
Usefulness of MALDI/TOF mass spectrometry of immunoprecipitated serum variant transthyretin in the diagnosis of familial amyloid polyneuropathy. | Tachibana N | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 1999 | PMID: 10611950 |
A new amyloidogenic transthyretin variant, [D38A], detected by electrospray ionization/mass spectrometry. | Kishikawa M | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 1999 | PMID: 10611949 |
[Detection and characterization of aberrant blood proteins and quantification of glycated hemoglobin by mass spectrometry]. | Shimizu A | Rinsho byori. The Japanese journal of clinical pathology | 1998 | PMID: 9627498 |
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Text-mined citations for rs1598844213 ...
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.