This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Ser50Arg. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affects the stability and function of the protein (PMID: 12874858, 17503405).
ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.210T>A (p.Ser70Arg)
Germline
Classification
Help
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.
(4)
Help
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.
Pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000371.4(TTR):c.210T>A (p.Ser70Arg)
Variation ID: 36890 Accession: VCV000036890.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31595129 (GRCh38) [ NCBI UCSC ] 18: 29175092 (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 Apr 4, 2013 May 1, 2024 Jan 11, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000371.4:c.210T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Ser70Arg missense NC_000018.10:g.31595129T>A NC_000018.9:g.29175092T>A NG_009490.1:g.8363T>A LRG_416:g.8363T>A LRG_416t1:c.210T>A LRG_416p1:p.Ser70Arg P02766:p.Ser70Arg - Protein change
- S70R
- Other names
- -
- Canonical SPDI
- NC_000018.10:31595128:T: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
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| TTR | - | - |
GRCh38 GRCh37 |
375 | 422 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 11, 2024 | RCV000030572.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 14, 2020 | RCV000517494.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 24, 2018 | RCV002415438.2 |
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
Help
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
Help
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
Help
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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|---|---|---|---|---|---|
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Pathogenic
(Dec 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000616210.2
First in ClinVar: Dec 19, 2017 Last updated: Sep 19, 2021 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Ser50Arg. This variant … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Ser50Arg. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affects the stability and function of the protein (PMID: 12874858, 17503405). (less)
|
|
|
Pathogenic
(Jul 29, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidogenic transthyretin amyloidosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053244.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 11, 2022 |
Comment:
Variant summary: The TTR c.210T>A (p.Ser70Arg) variant involves the alteration of a non-conserved nucleotide. Ser70 is located in the Transthyretin/hydroxyisourate hydrolase, superfamily domain and p.Ser70Ile … (more)
Variant summary: The TTR c.210T>A (p.Ser70Arg) variant involves the alteration of a non-conserved nucleotide. Ser70 is located in the Transthyretin/hydroxyisourate hydrolase, superfamily domain and p.Ser70Ile has been classified as pathogenic by our laboratory, indicateing Ser70 is critical for TTR function. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120430 control chromosomes. This variant has been reported in numerous ATTR patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
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Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Amyloidosis, hereditary systemic 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000769143.7
First in ClinVar: Apr 04, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 70 of the TTR protein (p.Ser70Arg). … (more)
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 70 of the TTR protein (p.Ser70Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). It is commonly reported in individuals of Mexico ancestry (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). This variant is also known as in other populations (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). ClinVar contains an entry for this variant (Variation ID: 36890). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Jul 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002725959.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.S70R pathogenic mutation (also known as c.210T>A and S50R), located in coding exon 3 of the TTR gene, results from a T to A … (more)
The p.S70R pathogenic mutation (also known as c.210T>A and S50R), located in coding exon 3 of the TTR gene, results from a T to A substitution at nucleotide position 210. The serine at codon 70 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been described in numerous unrelated families of Japanese, Caucasian, and Mexican ancestry with familial amyloid polyneuropathy (Ueno S et al. Biochem. Biophys. Res. Commun. 1990 Jun;169(3):1117-21; Munar-Qués M et al. Amyloid 2007 Jun;14(2):147-52; González-Duarte A et al. Amyloid 2013 Dec;20(4):221-5). Of note, the nucleotide changes observed in these studies, which all result in the same p.S70R amino acid substitution, include c.210T>G, c.208A>C, and c.210T>A, respectively. In one Italian study, three of four individuals from two unrelated families with this mutation were observed to have a mixed neurologic and cardiac phenotype, while one individual had a primarily neurologic phenotype (Rapezzi C et al. Eur. Heart J. 2013 Feb; 34(7):520-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
Comment:
Comment:
Variant summary: The TTR c.210T>A (p.Ser70Arg) variant involves the alteration of a non-conserved nucleotide. Ser70 is located in the Transthyretin/hydroxyisourate hydrolase, superfamily domain and p.Ser70Ile has been classified as pathogenic by our laboratory, indicateing Ser70 is critical for TTR function. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120430 control chromosomes. This variant has been reported in numerous ATTR patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 70 of the TTR protein (p.Ser70Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). It is commonly reported in individuals of Mexico ancestry (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). This variant is also known as in other populations (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). ClinVar contains an entry for this variant (Variation ID: 36890). 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%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.S70R pathogenic mutation (also known as c.210T>A and S50R), located in coding exon 3 of the TTR gene, results from a T to A substitution at nucleotide position 210. The serine at codon 70 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been described in numerous unrelated families of Japanese, Caucasian, and Mexican ancestry with familial amyloid polyneuropathy (Ueno S et al. Biochem. Biophys. Res. Commun. 1990 Jun;169(3):1117-21; Munar-Qués M et al. Amyloid 2007 Jun;14(2):147-52; González-Duarte A et al. Amyloid 2013 Dec;20(4):221-5). Of note, the nucleotide changes observed in these studies, which all result in the same p.S70R amino acid substitution, include c.210T>G, c.208A>C, and c.210T>A, respectively. In one Italian study, three of four individuals from two unrelated families with this mutation were observed to have a mixed neurologic and cardiac phenotype, while one individual had a primarily neurologic phenotype (Rapezzi C et al. Eur. Heart J. 2013 Feb; 34(7):520-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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. |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Ser50Arg. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affects the stability and function of the protein (PMID: 12874858, 17503405).
Comment:
Variant summary: The TTR c.210T>A (p.Ser70Arg) variant involves the alteration of a non-conserved nucleotide. Ser70 is located in the Transthyretin/hydroxyisourate hydrolase, superfamily domain and p.Ser70Ile has been classified as pathogenic by our laboratory, indicateing Ser70 is critical for TTR function. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120430 control chromosomes. This variant has been reported in numerous ATTR patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 70 of the TTR protein (p.Ser70Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). It is commonly reported in individuals of Mexico ancestry (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). This variant is also known as in other populations (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). ClinVar contains an entry for this variant (Variation ID: 36890). 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%. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.S70R pathogenic mutation (also known as c.210T>A and S50R), located in coding exon 3 of the TTR gene, results from a T to A substitution at nucleotide position 210. The serine at codon 70 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been described in numerous unrelated families of Japanese, Caucasian, and Mexican ancestry with familial amyloid polyneuropathy (Ueno S et al. Biochem. Biophys. Res. Commun. 1990 Jun;169(3):1117-21; Munar-Qués M et al. Amyloid 2007 Jun;14(2):147-52; González-Duarte A et al. Amyloid 2013 Dec;20(4):221-5). Of note, the nucleotide changes observed in these studies, which all result in the same p.S70R amino acid substitution, include c.210T>G, c.208A>C, and c.210T>A, respectively. In one Italian study, three of four individuals from two unrelated families with this mutation were observed to have a mixed neurologic and cardiac phenotype, while one individual had a primarily neurologic phenotype (Rapezzi C et al. Eur. Heart J. 2013 Feb; 34(7):520-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| THAOS: gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease. | Wixner J | Orphanet journal of rare diseases | 2014 | PMID: 24767411 |
| Clinical proteome informatics workbench detects pathogenic mutations in hereditary amyloidoses. | Dasari S | Journal of proteome research | 2014 | PMID: 24650283 |
| Description of transthyretin S50A, S52P and G47A mutations in familial amyloidosis polyneuropathy. | González-Duarte A | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2013 | PMID: 24053266 |
| 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 |
| Delayed diagnosis of transthyretin amyloidosis with a novel mutation (c.210T>A) in the transthyretin gene. | Dekmezian MS | Journal of the American Academy of Dermatology | 2013 | PMID: 23317988 |
| 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 |
| Familial amyloidosis with polyneuropathy associated with TTR Ser50Arg mutation. | González-Duarte A | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2012 | PMID: 22928869 |
| Variable presentations of TTR-related familial amyloid polyneuropathy in seventeen patients. | Cappellari M | Journal of the peripheral nervous system : JPNS | 2011 | PMID: 21692911 |
| A case of atypical amyloid polyneuropathy with predominant upper-limb involvement with the diagnosis unexpectedly found at lung operation. | Shirota Y | Internal medicine (Tokyo, Japan) | 2010 | PMID: 20686303 |
| Biochemical characterisation of amyloid by endomyocardial biopsy. | Benson MD | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2009 | PMID: 19291509 |
| Familial amyloid polyneuropathy associated with TTRSer50Arg mutation in two Iberian families presenting a novel single base change in the mutant gene. | Munar-Qués M | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2007 | PMID: 17577688 |
| Genetic microheterogeneity of human transthyretin detected by IEF. | Altland K | Electrophoresis | 2007 | PMID: 17503405 |
| Ten years of experience with liver transplantation for familial amyloid polyneuropathy in Japan: outcomes of living donor liver transplantations. | Takei Y | Internal medicine (Tokyo, Japan) | 2005 | PMID: 16357452 |
| The hereditary amyloidoses. | Benson MD | Best practice & research. Clinical rheumatology | 2003 | PMID: 15123043 |
| Polyacrylamide gel electrophoresis followed by sodium dodecyl sulfate gradient polyacrylamide gel electrophoresis for the study of the dimer to monomer transition of human transthyretin. | Altland K | Electrophoresis | 2003 | PMID: 12874858 |
| Familial transthyretin-type amyloid polyneuropathy in Japan: clinical and genetic heterogeneity. | Ikeda S | Neurology | 2002 | PMID: 11940682 |
| Amyloid polyneuropathy with transthyretin Arg50 in a Japanese case from Osaka. | Takahashi N | Journal of the neurological sciences | 1992 | PMID: 1335038 |
| Two novel variants of transthyretin identified in Japanese cases with familial amyloidotic polyneuropathy: transthyretin (Glu42 to Gly) and transthyretin (Ser50 to Arg). | Ueno S | Biochemical and biophysical research communications | 1990 | PMID: 2363717 |
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Text-mined citations for rs121918076 ...
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the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.