ClinVar Genomic variation as it relates to human health
NM_139027.6(ADAMTS13):c.559G>C (p.Asp187His)
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.
Likely pathogenic(3); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_139027.6(ADAMTS13):c.559G>C (p.Asp187His)
Variation ID: 632074 Accession: VCV000632074.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.2 9: 133426218 (GRCh38) [ NCBI UCSC ] 9: 136291338 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 27, 2019 Oct 8, 2024 Feb 19, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_139027.6:c.559G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_620596.2:p.Asp187His missense NM_139025.5:c.559G>C NP_620594.1:p.Asp187His missense NM_139026.6:c.559G>C NP_620595.1:p.Asp187His missense NR_024514.3:n.762G>C non-coding transcript variant NC_000009.12:g.133426218G>C NC_000009.11:g.136291338G>C NG_011934.2:g.16880G>C LRG_544:g.16880G>C LRG_544t1:c.559G>C LRG_544p1:p.Asp187His - Protein change
- D187H
- Other names
- -
- Canonical SPDI
- NC_000009.12:133426217:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00020 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
Trans-Omics for Precision Medicine (TOPMed) 0.00041
The Genome Aggregation Database (gnomAD) 0.00043
Exome Aggregation Consortium (ExAC) 0.00047
The Genome Aggregation Database (gnomAD), exomes 0.00047
- 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. |
|||
ADAMTS13 | - | - |
GRCh38 GRCh38 GRCh37 |
748 | 821 |
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
May 22, 2023 | RCV000778929.12 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Sep 7, 2022 | RCV001507763.13 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Feb 19, 2024 | RCV003994114.1 | |
ADAMTS13-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Sep 11, 2024 | RCV004754560.1 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(May 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Upshaw-Schulman syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915344.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ADAMTS13 c.559G>C (p.Asp187His) variant has been reported in two studies in which it was found in a compound heterozygous state in one patient and … (more)
The ADAMTS13 c.559G>C (p.Asp187His) variant has been reported in two studies in which it was found in a compound heterozygous state in one patient and in a heterozygous state in a second patient in whom an additional variant was not identified, both affected with familial thrombotic thrombocytopenia purpura, onset of which was triggered by pregnancy (De Cock et al. 2015; Delmas et al. 2015). The p.Asp187His variant was identified in 19 of 21,658 control alleles (Lotta et al. 2013; de Vries et al. 2015; Pagliari et al. 2016) and is reported at a frequency of 0.00121 in the Latino population of the Exome Aggregation Consortium. In vitro studies conducted in human embryonic kidney cells showed that the variant reduced ADAMTS13 antigen levels (to 58% of wild type) and activity (to 19% of wild type) as well as reduced the catalytic efficiency of the enzyme, impaired proteolysis of von Willebrand factor, destablized calcium binding, and impaired protein secretion (De Cock et al. 2015; Pagliari et al. 2016). In addition, expression of the p.Asp187His form of the protein, unlike the wild type form, could not rescue the thrombotic thrombocytopenia phenotype of ADAMTS13 null mice (De Cock et al. 2015). In vitro studies also demonstrated the negative effect of another variant at the same position (p.Asp187Ala), providing additional evidence of the functional role of Asp187 in a high affinity calcium binding site important for von Willebrand factor binding and proteolysis (Gardner et al. 2009; de Groot et al. 2010). Based on the evidence, the p.Asp187His variant is classified as likely pathogenic for familial thrombotic thrombocytopenia purpura. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
Uncertain significance
(Aug 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Upshaw-Schulman syndrome
Affected status: yes
Allele origin:
paternal
|
Baylor Genetics
Accession: SCV001526131.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
Likely pathogenic
(Jan 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713511.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PM1, PP3
Number of individuals with the variant: 2
|
|
Likely pathogenic
(Jan 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002098329.1
First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022 |
|
|
Uncertain significance
(Sep 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003261538.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 187 of the ADAMTS13 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 187 of the ADAMTS13 protein (p.Asp187His). This variant is present in population databases (rs148312697, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with thrombotic thrombocytopenic purpura (PMID: 25442981, 26081109, 30312976). ClinVar contains an entry for this variant (Variation ID: 632074). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ADAMTS13 function (PMID: 25442981, 27802307). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(May 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002512853.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
Reported in a female with pregnancy-onset TTP who was later found to have reduced ADAMTS13 activity outside the pregnancy period in published literature (De Cock … (more)
Reported in a female with pregnancy-onset TTP who was later found to have reduced ADAMTS13 activity outside the pregnancy period in published literature (De Cock et al., 2015); however, a second ADAMTS13 variant was not identified; Observed with a canonical splice site variant in a pregnant female presenting w/ pre-eclampsia, severe thrombocytopenia, and reduced ADAMTS13 activity in published literature (Delmas et al., 2015), although it is not known if these variants were present on the same allele (in cis) or on opposite alleles (in trans); Identified in a heterozygous child presenting with atypical hemolytic uremic syndrome and nephrotic syndrome in published literature (Bello-Marquez et al., 2020); however, no second ADAMTS13 variant was reported, ADAMTS13 activity was reported to be normal, and variants in other genes were also identified; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect on protein secretion and activity (De Cock et al., 2015; Pagliari et al., 2016); This variant is associated with the following publications: (PMID: 27802307, 29669506, 25934476, 23648131, 25442981, 26081109, 32779691, 19047683, 20647566, 34426522) (less)
|
|
Uncertain significance
(May 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Upshaw-Schulman syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004238936.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
Uncertain significance
(Feb 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813402.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: ADAMTS13 c.559G>C (p.Asp187His) results in a non-conservative amino acid change located in the Peptidase M12B, ADAM/reprolysin domain (IPR001590) of the encoded protein sequence. … (more)
Variant summary: ADAMTS13 c.559G>C (p.Asp187His) results in a non-conservative amino acid change located in the Peptidase M12B, ADAM/reprolysin domain (IPR001590) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 1613864 control chromosomes in the gnomAD database, including 1 homozygote. c.559G>C has been reported in the literature in individuals affected with Thrombotic Thrombocytopenic Purpura or atypical hemolytic uremic syndrome without strong evidence of causality (De Cock_2015, Delmas_2015, Pagliari_2016, Wilson_2020, Bello-Marquez_2021). These reports do not provide unequivocal conclusions about association of the variant with Thrombotic Thrombocytopenic Purpura. At least two publications reports experimental evidence evaluating an impact on protein function, finding that the variant effect results in 10%-<30% of normal activity in vitro (De Cock_2015, Pagliari_2016). The following publications have been ascertained in the context of this evaluation (PMID: 25442981, 27802307, 26081109, 32779691, 35372954). ClinVar contains an entry for this variant (Variation ID: 632074). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
Upshaw-Schulman syndrome
Affected status: yes
Allele origin:
unknown
|
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002515518.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Comment:
Submitted to GoldVariant by Prof Kathleen Freson from Center for Molecular and Vascular Biology, Leuven, Belgium
|
Clinical Features:
Deep Vein Thrombosis (present) , arterial thrombosis (present)
|
|
Uncertain significance
(Sep 11, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ADAMTS13-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005351973.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ADAMTS13 c.559G>C variant is predicted to result in the amino acid substitution p.Asp187His. This variant has been reported in individuals with pregnancy-onset thrombotic thrombocytopenic … (more)
The ADAMTS13 c.559G>C variant is predicted to result in the amino acid substitution p.Asp187His. This variant has been reported in individuals with pregnancy-onset thrombotic thrombocytopenic purpura (De Cock et al. 2015. PubMed ID: 25442981; Patient C, Delmas et al. 2015. PubMed ID: 26081109). This variant was also identified in individuals with deep vein thrombosis (Lotta et al. 2013. PubMed ID: 23648131; Pagliari et al. 2016. PubMed ID: 27802307). Of note, this variant was also identified in the control population (Pagliari et al. 2016. PubMed ID: 27802307). A genome-wide association study of ADAMTS13 activity in a population-based cohort study determined that the c.559G>C variant was rare and was associated with ADAMTS13 activity (Referenced as rs148312697, de Vries et al. 2015. PubMed ID: 25934476). Additional functional studies of this variant showed that it leads to decreased ADAMTS13 activity and secretion (Gardner et al. 2009. PubMed ID: 19047683; De Cock et al. 2015. PubMed ID: 25442981; Pagliari et al. 2016. PubMed ID: 27802307). Another missense variant impacting the same amino acid (p.Asp187Ala) has also been shown reduced proteolytic function of ADAMTS13 (Groot et al. 2010. PubMed ID: 20647566). This variant is reported in 0.090% of alleles in individuals of Latino descent in gnomAD. This variant has conflicting interpretations in the ClinVar database, ranging from uncertain significance to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/632074/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
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 |
---|---|---|---|---|
Nephrotic syndrome associated with primary atypical hemolytic uremic syndrome. | Bello-Marquez DC | Jornal brasileiro de nefrologia | 2021 | PMID: 32779691 |
Beyond Panel-Based Testing: Exome Analysis Increases Sensitivity for Diagnosis of Genetic Kidney Disease. | Wilson PC | Kidney360 | 2020 | PMID: 35372954 |
ADAMTS13 Gene Mutations Influence ADAMTS13 Conformation and Disease Age-Onset in the French Cohort of Upshaw-Schulman Syndrome. | Joly BS | Thrombosis and haemostasis | 2018 | PMID: 30312976 |
Next-Generation Sequencing and In Vitro Expression Study of ADAMTS13 Single Nucleotide Variants in Deep Vein Thrombosis. | Pagliari MT | PloS one | 2016 | PMID: 27802307 |
Incidence of obstetrical thrombotic thrombocytopenic purpura in a retrospective study within thrombocytopenic pregnant women. A difficult diagnosis and a treatable disease. | Delmas Y | BMC pregnancy and childbirth | 2015 | PMID: 26081109 |
Genetic variants in the ADAMTS13 and SUPT3H genes are associated with ADAMTS13 activity. | de Vries PS | Blood | 2015 | PMID: 25934476 |
The novel ADAMTS13-p.D187H mutation impairs ADAMTS13 activity and secretion and contributes to thrombotic thrombocytopenic purpura in mice. | De Cock E | Journal of thrombosis and haemostasis : JTH | 2015 | PMID: 25442981 |
Next-generation sequencing study finds an excess of rare, coding single-nucleotide variants of ADAMTS13 in patients with deep vein thrombosis. | Lotta LA | Journal of thrombosis and haemostasis : JTH | 2013 | PMID: 23648131 |
The ADAMTS13 metalloprotease domain: roles of subsites in enzyme activity and specificity. | de Groot R | Blood | 2010 | PMID: 20647566 |
A functional calcium-binding site in the metalloprotease domain of ADAMTS13. | Gardner MD | Blood | 2009 | PMID: 19047683 |
Text-mined citations for rs148312697 ...
HelpRecord last updated Oct 13, 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.