ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.210T>G (p.Ser70Arg)
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.210T>G (p.Ser70Arg)
Variation ID: 13429 Accession: VCV000013429.6
- 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 Feb 14, 2024 Mar 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.210T>G 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>G NC_000018.9:g.29175092T>G NG_009490.1:g.8363T>G LRG_416:g.8363T>G LRG_416t1:c.210T>G LRG_416p1:p.Ser70Arg P02766:p.Ser70Arg - Protein change
- S70R
- Other names
- S50R
- Canonical SPDI
- NC_000018.10:31595128:T: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 (3) |
criteria provided, single submitter
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Dec 15, 2018 | RCV000014371.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 5, 2022 | RCV002415415.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 7, 2023 | RCV003480030.1 |
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 07, 2023)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225038.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PM1, PM2, PS1, PS4
Number of individuals with the variant: 1
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Pathogenic
(Dec 15, 2018)
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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: SCV000950793.3
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. A different variant (c.210T>A) giving rise to the same protein effect observed here (p.Ser70Arg) has … (more)
For these reasons, this variant has been classified as Pathogenic. A different variant (c.210T>A) giving rise to the same protein effect observed here (p.Ser70Arg) has been determined to be pathogenic (PMID: 24053266, 22745357, 22928869). This suggests that this variant is also likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class Class C0"). This variant has been observed in several individuals with amyloidosis (PMID: 23713495, 1335038, 2363717, 27273296).  This variant is also known as p.Ser50Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 13429). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 70 of the TTR protein (p.Ser70Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. (less)
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Pathogenic
(Jul 05, 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: SCV002725230.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.S70R pathogenic mutation (also known as c.210T>G and S50R), located in coding exon 3 of the TTR gene, results from a T to G … (more)
The p.S70R pathogenic mutation (also known as c.210T>G and S50R), located in coding exon 3 of the TTR gene, results from a T to G 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
(Oct 01, 1992)
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no assertion criteria provided
Method: literature only
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AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034620.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a Japanese kindred with autosomal dominant amyloid polyneuropathy (105210), Ueno et al. (1990) found a T-to-G transversion at position 3252 in exon 3 of … (more)
In a Japanese kindred with autosomal dominant amyloid polyneuropathy (105210), Ueno et al. (1990) found a T-to-G transversion at position 3252 in exon 3 of the TTR gene resulting in replacement of serine by arginine at position 50 (S50R). The mutant was discovered by randomly sequencing recombinant clones containing the entire length of each of the 4 exons selectively amplified by PCR. The base change produced a change in restriction site RFLPs, and allele-specific oligonucleotide hybridization confirmed the base change. Takahashi et al. (1992) described the same mutation in a member of another family. (less)
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Pathogenic
(Apr 03, 2015)
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no assertion criteria provided
Method: clinical testing
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Amyloidogenic transthyretin amyloidosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053245.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
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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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Inflammatory state exists in familial amyloid polyneuropathy that may be triggered by mutated transthyretin. | Suenaga G | Scientific reports | 2017 | PMID: 28484271 |
Cerebral amyloid angiopathy in posttransplant patients with hereditary ATTR amyloidosis. | Sekijima Y | Neurology | 2016 | PMID: 27466465 |
Cutaneous Manifestations of Familial Transthyretin Amyloid Polyneuropathy. | Lanoue J | The American Journal of dermatopathology | 2016 | PMID: 26959691 |
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 |
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 |
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 |
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 |
Text-mined citations for rs121918076 ...
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.