ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.128G>A (p.Ser43Asn)
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.128G>A (p.Ser43Asn)
Variation ID: 661615 Accession: VCV000661615.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31592954 (GRCh38) [ NCBI UCSC ] 18: 29172917 (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 Oct 31, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.128G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Ser43Asn missense NC_000018.10:g.31592954G>A NC_000018.9:g.29172917G>A NG_009490.1:g.6188G>A LRG_416:g.6188G>A LRG_416t1:c.128G>A LRG_416p1:p.Ser43Asn - Protein change
- S43N
- Other names
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- Canonical SPDI
- NC_000018.10:31592953:G:A
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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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Oct 31, 2022 | RCV000819070.17 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 29, 2020 | RCV001811504.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 31, 2022 | RCV002381854.8 |
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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Likely pathogenic
(Apr 29, 2020)
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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: SCV001471425.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The TTR c.128G>A; p.Ser43Asn variant, also known as Ser23Asn, is reported in the literature in multiple individuals affected with transthyretin-related amyloidosis (Castano 2012, Ihse 2013, … (more)
The TTR c.128G>A; p.Ser43Asn variant, also known as Ser23Asn, is reported in the literature in multiple individuals affected with transthyretin-related amyloidosis (Castano 2012, Ihse 2013, Mueller 2010, Rapezzi 2013). This variant is reported in ClinVar (Variation ID: 661615), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Functional analyses demonstrate reduced monomer stability and positive for amyloid formation on endomyocardial biopsies from multiple patients (Castano 2012, Mueller 2010). The serine at codon 43 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Based on available information, this variant is considered to be likely pathogenic. References: Castano A et al. Technetium pyrophosphate myocardial uptake and peripheral neuropathy in a rare variant of familial transthyretin (TTR) amyloidosis (Ser23Asn): a case report and literature review. Amyloid. 2012;19(1):41–46. Ihse E et al. Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. Amyloid. 2013;20(3):142–150. Mueller II et al. Restrictive cardiomyopathy in inherited ATTR amyloidosis (TTR-Ser23Asn) in a patient of German-Italian extraction. BMJ Case Rep. 2010;2010:bcr06.2009.2032. Rapezzi C et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013;34(7):520–528. (less)
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Pathogenic
(May 04, 2022)
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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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Mendelics
Accession: SCV002519917.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Likely pathogenic
(Aug 31, 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: SCV002691635.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.S43N variant (also known as c.128G>A), located in coding exon 2 of the TTR gene, results from a G to A substitution at nucleotide … (more)
The p.S43N variant (also known as c.128G>A), located in coding exon 2 of the TTR gene, results from a G to A substitution at nucleotide position 128. The serine at codon 43 is replaced by asparagine, an amino acid with highly similar properties. This alteration, which is also known as p.S23N, has been reported in individuals with a clinical diagnosis of transthyretin (TTR) amyloidosis, as well as TTR amyloidosis cohorts (Connors LH et al. Amyloid, 1999 Jun;6:114-8; Mueller II et al. BMJ Case Rep, 2010 Mar;2010:[ePub ahead of print]; Castaño A et al. Amyloid, 2012 Mar;19:41-6; Rapezzi C et al. Eur Heart J, 2013 Feb;34:520-8; Ihse E et al. Amyloid, 2013 Sep;20:142-50; Liu N et al. Sci Rep, 2017 09;7:10676; Waddington-Cruz M et al. J Peripher Nerv Syst, 2021 06;26:160-166; Papathanasiou M et al. Mol Genet Genomic Med, 2021 12;9:e1581). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 31, 2022)
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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: SCV000959712.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 43 of the TTR protein (p.Ser43Asn). … (more)
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 43 of the TTR protein (p.Ser43Asn). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 661615). This variant is also known as p.Ser23Asn. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 10439117, 22149423, 22400056, 23713495, 26428663, 28878402). This variant is not present in population databases (gnomAD no frequency). (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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Feasibility of assessing progression of transthyretin amyloid polyneuropathy using nerve conduction studies: Findings from the Transthyretin Amyloidosis Outcomes Survey (THAOS). | Waddington-Cruz M | Journal of the peripheral nervous system : JPNS | 2021 | PMID: 33844361 |
Rare variant (p.Ser43Asn) of familial transthyretin amyloidosis associated with isolated cardiac phenotype: A case series with literature review. | Papathanasiou M | Molecular genetics & genomic medicine | 2021 | PMID: 33345470 |
Genetic Mechanisms Contribute to the Development of Heart Failure in Patients with Atrioventricular Block and Right Ventricular Apical Pacing. | Liu N | Scientific reports | 2017 | PMID: 28878402 |
The Val142Ile transthyretin cardiac amyloidosis: not only an Afro-American pathogenic variant? A single-centre Italian experience. | Cappelli F | Journal of cardiovascular medicine (Hagerstown, Md.) | 2016 | PMID: 26428663 |
Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. | Ihse E | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2013 | PMID: 23713495 |
Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. | Rapezzi C | European heart journal | 2013 | PMID: 22745357 |
Technetium pyrophosphate myocardial uptake and peripheral neuropathy in a rare variant of familial transthyretin (TTR) amyloidosis (Ser23Asn): a case report and literature review. | Castaño A | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2012 | PMID: 22149423 |
Restrictive cardiomyopathy in inherited ATTR amyloidosis (TTR-Ser23Asn) in a patient of German-Italian extraction. | Mueller II | BMJ case reports | 2010 | PMID: 22400056 |
A new transthyretin variant (Ser23Asn) associated with familial amyloidosis in a Portuguese patient. | Connors LH | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 1999 | PMID: 10439117 |
Text-mined citations for rs1598844112 ...
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.