ClinVar Genomic variation as it relates to human health
NM_139027.6(ADAMTS13):c.1423C>T (p.Pro475Ser)
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.
Uncertain significance(1); Benign(2); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_139027.6(ADAMTS13):c.1423C>T (p.Pro475Ser)
Variation ID: 5814 Accession: VCV000005814.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.2 9: 133436943 (GRCh38) [ NCBI UCSC ] 9: 136302063 (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 26, 2015 Feb 20, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_139027.6:c.1423C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_620596.2:p.Pro475Ser missense NM_139025.5:c.1423C>T NP_620594.1:p.Pro475Ser missense NM_139026.6:c.1330C>T NP_620595.1:p.Pro444Ser missense NC_000009.12:g.133436943C>T NC_000009.11:g.136302063C>T NG_011934.2:g.27605C>T LRG_544:g.27605C>T LRG_544t1:c.1423C>T LRG_544p1:p.Pro475Ser Q76LX8:p.Pro475Ser - Protein change
- P475S, P444S
- Other names
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- Canonical SPDI
- NC_000009.12:133436942:C:T
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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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0.00439 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00232
Trans-Omics for Precision Medicine (TOPMed) 0.00261
1000 Genomes Project 30x 0.00375
1000 Genomes Project 0.00439
The Genome Aggregation Database (gnomAD), exomes 0.00582
Exome Aggregation Consortium (ExAC) 0.00733
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 | ||
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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. |
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ADAMTS13 | - | - |
GRCh38 GRCh38 GRCh37 |
731 | 792 |
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. |
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Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000006170.12 | |
Likely benign (1) |
criteria provided, single submitter
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- | RCV000251648.7 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 22, 2024 | RCV000767050.5 |
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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Likely benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000315859.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial Thrombotic Thrombocytopenia Purpura
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000478321.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Apr 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617792.2
First in ClinVar: Dec 19, 2017 Last updated: Apr 17, 2019 |
Comment:
Often reported in the literature as a polymorphism with a suspected northeastern Asian origin of the variant (Nakagawa et al., 2016; Tso et al., 2020); … (more)
Often reported in the literature as a polymorphism with a suspected northeastern Asian origin of the variant (Nakagawa et al., 2016; Tso et al., 2020); Reported in a deceased female infant with diarrhea negative hemolytic uremic syndrome and ADAMTS13 activity that was 54% of normal levels (Choi et al., 2011); Published functional crystal structure studies demonstrate that the P475S mutant destabilizes the protein leading to reduced substrate affinity and moderately reduced catalytic efficiency of the ADAMTS13 enzyme (Akiyama et al., 2013); Published functional cell transfection studies demonstrate the P475S variant resulted in very low enzyme activity (Kokame et al., 2002); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in 2.024% (642/31714 alleles) individuals of Latino background and 1.524% (273/17908 alleles) individuals of East Asian background in the gnomAD dataset, including multiple unrelated homozygous individuals (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12195022, 23715102, 19847791, 18665921, 27497325, 23621748, 22768050, 12181489, 21676167, 18581589, 21488199, 29669506, 29304523, 32588586) (less)
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Benign
(Jan 22, 2024)
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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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Invitae
Accession: SCV003246220.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Upshaw-Schulman syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001137945.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Sep 03, 2002)
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no assertion criteria provided
Method: literature only
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THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026352.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 05, 2020 |
Comment on evidence:
Kokame et al. (2002) reported a Japanese family in which a pro475-to-ser (P475S) mutation of the ADAMTS13 gene caused reduction in VWFCP activity, although that … (more)
Kokame et al. (2002) reported a Japanese family in which a pro475-to-ser (P475S) mutation of the ADAMTS13 gene caused reduction in VWFCP activity, although that activity was not completely abrogated. The proband, who had Schulman-Upshaw syndrome (TTP; 274150), had VWFCP activity below 3% of normal; VWFCP activity of the proband's mother and sister were 36% and 30% of normal, respectively, and the father had activity 5.6% of normal. The father and daughter were heterozygous for the P475S mutation. Studies in HeLa cells demonstrated that this mutant form of VWFCP, like the gln449-to-ter (Q449X; 604134.0013) form, was normally secreted but showed minimal activity. Genotype analysis of 364 Japanese subjects revealed that P475S is heterozygous in 9.6% of individuals, suggesting that approximately 10% of the Japanese population possesses reduced VWFCP activity. Thus, this mutation represents a SNP associated with alterations in VWFCP activity that may be a risk factor for thrombotic disorders. (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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ADAMTS13 activity and genetic mutations in Japan. | Miyata T | Hamostaseologie | 2013 | PMID: 23715102 |
Crystal structure and enzymatic activity of an ADAMTS-13 mutant with the East Asian-specific P475S polymorphism. | Akiyama M | Journal of thrombosis and haemostasis : JTH | 2013 | PMID: 23621748 |
Characterization of coding synonymous and non-synonymous variants in ADAMTS13 using ex vivo and in silico approaches. | Edwards NC | PloS one | 2012 | PMID: 22768050 |
Polymorphisms and mutations of ADAMTS13 in the Japanese population and estimation of the number of patients with Upshaw-Schulman syndrome. | Kokame K | Journal of thrombosis and haemostasis : JTH | 2011 | PMID: 21676167 |
ADAMTS13 P475S polymorphism causes a lowered enzymatic activity and urea lability in vitro. | Akiyama M | Journal of thrombosis and haemostasis : JTH | 2008 | PMID: 18665921 |
Frequency of Pro475Ser polymorphism of ADAMTS13 gene and its association with ADAMTS-13 activity in the Korean population. | Jang MJ | Yonsei medical journal | 2008 | PMID: 18581589 |
Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. | Kokame K | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 12181489 |
Text-mined citations for rs11575933 ...
HelpRecord last updated Mar 11, 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.