ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.113A>G (p.Asp38Gly)
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.113A>G (p.Asp38Gly)
Variation ID: 13463 Accession: VCV000013463.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31592939 (GRCh38) [ NCBI UCSC ] 18: 29172902 (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 Jan 31, 2015 Feb 14, 2024 May 25, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.113A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Asp38Gly missense NC_000018.10:g.31592939A>G NC_000018.9:g.29172902A>G NG_009490.1:g.6173A>G LRG_416:g.6173A>G LRG_416t1:c.113A>G LRG_416p1:p.Asp38Gly P02766:p.Asp38Gly - Protein change
- D38G
- Other names
- D18G
- Canonical SPDI
- NC_000018.10:31592938: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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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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May 25, 2021 | RCV000036373.9 | |
Pathogenic (1) |
no assertion criteria provided
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Dec 1, 1996 | RCV000014405.18 |
Submissions - Germline
Classification
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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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Pathogenic
(Mar 01, 2012)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060025.6
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
The Asp38Gly variant (TTR) has been identified in 4 individuals with leptomening eal/CNS-related TTR amyloidosis, including one individual with restrictive cardi omyopathy (note, the variant … (more)
The Asp38Gly variant (TTR) has been identified in 4 individuals with leptomening eal/CNS-related TTR amyloidosis, including one individual with restrictive cardi omyopathy (note, the variant is also referred to as Asp18Gly; Vidal 1996, Jin 20 04, Barreiros 2010). In addition, this variant segregates with disease in 4 affe cted family members, including one obligate carrier, and was absent from 80 cont rol chromosomes (Vidal 1996, Jin 2004). Furthermore, functional analyses showed the Asp38Gly variant results in an abnormal protein that is highly destabilized, has diminished secretion, and has abnormal cellular localization (Hammarstrom 2 003, Sekijima 2005). In summary, the Asp38Gly variant is highly likely to be pat hogenic based upon correlation with clinical phenotype, segregation with disease , and functional studies. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 25, 2021)
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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: SCV002119879.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp38 amino acid residue in TTR. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp38 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23126592, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 8579098, 20209591). It has also been observed to segregate with disease in related individuals. This variant is also known as D18G. ClinVar contains an entry for this variant (Variation ID: 13463). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 38 of the TTR protein (p.Asp38Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. (less)
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Pathogenic
(Dec 01, 1996)
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no assertion criteria provided
Method: literature only
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AMYLOIDOSIS, LEPTOMENINGEAL, TRANSTHYRETIN-RELATED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034654.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 29, 2016 |
Comment on evidence:
In a Hungarian family with meningocerebrovascular amyloidosis (see 105210), Garzuly et al. (1996) and Vidal et al. (1996) identified a mutation in the transthyretin gene, … (more)
In a Hungarian family with meningocerebrovascular amyloidosis (see 105210), Garzuly et al. (1996) and Vidal et al. (1996) identified a mutation in the transthyretin gene, resulting in an asp18-to-gly (D18G) substitution. (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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A transthyretin variant, Asp18Asn, associated with amyloid cardiomyopathy: a new African-American variant? | Quarta CC | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2012 | PMID: 23126592 |
Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. | Barreiros AP | Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society | 2010 | PMID: 20209591 |
Familial leptomeningeal amyloidosis with a transthyretin variant Asp18Gly representing repeated subarachnoid haemorrhages with superficial siderosis. | Jin K | Journal of neurology, neurosurgery, and psychiatry | 2004 | PMID: 15377697 |
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 |
D18G transthyretin is monomeric, aggregation prone, and not detectable in plasma and cerebrospinal fluid: a prescription for central nervous system amyloidosis? | Hammarström P | Biochemistry | 2003 | PMID: 12779320 |
Transthyretin mutations in hyperthyroxinemia and amyloid diseases. | Saraiva MJ | Human mutation | 2001 | PMID: 11385707 |
Familial meningocerebrovascular amyloidosis, Hungarian type, with mutant transthyretin (TTR Asp18Gly). | Garzuly F | Neurology | 1996 | PMID: 8960746 |
Meningocerebrovascular amyloidosis associated with a novel transthyretin mis-sense mutation at codon 18 (TTRD 18G). | Vidal R | The American journal of pathology | 1996 | PMID: 8579098 |
Text-mined citations for rs121918098 ...
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.