9-133454548-C-T

Position:

chr9-133454548-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PP5_Very_StrongBP4

The ENST00000355699.7(ADAMTS13):c.3178C>T(p.Arg1060Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,608,810 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1060Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00085 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

ADAMTS13
ENST00000355699.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19O:1

Conservation

PhyloP100: 3.19

Variant links:

Genes affected

ADAMTS13 (HGNC:1366): (ADAM metallopeptidase with thrombospondin type 1 motif 13) This gene encodes a member of a family of proteins containing several distinct regions, including a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. The enzyme encoded by this gene specifically cleaves von Willebrand Factor (vWF). Defects in this gene are associated with thrombotic thrombocytopenic purpura. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ADAMTS13 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a domain TSP type-1 7 (size 56) in uniprot entity ATS13_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000355699.7

PP5

Variant 9-133454548-C-T is Pathogenic according to our data. Variant chr9-133454548-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133454548-C-T is described in UniProt as null. Variant chr9-133454548-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0662958). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS13	NM_139027.6 linkuse as main transcript	c.3178C>T	p.Arg1060Trp	missense_variant	24/29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7 linkuse as main transcript	c.3178C>T	p.Arg1060Trp	missense_variant	24/29	1	NM_139027.6	ENSP00000347927	A2	Q76LX8-2

Frequencies

GnomAD3 genomes

AF:

0.000854

AC:

130

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000828

AC:

203

AN:

245122

Hom.:

AF XY:

0.000922

AC XY:

123

AN XY:

133454

show subpopulations

Gnomad AFR exome

AF:

0.000439

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000687

Gnomad FIN exome

AF:

0.000271

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.00112

AC:

1631

AN:

1456452

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

768

AN XY:

724836

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000742

Gnomad4 FIN exome

AF:

0.000517

Gnomad4 NFE exome

AF:

0.00132

Gnomad4 OTH exome

AF:

0.000663

GnomAD4 genome

AF:

0.000853

AC:

130

AN:

152358

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00135

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000844

Hom.:

Bravo

AF:

0.000865

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000924

AC:

112

EpiCase

AF:

0.000709

EpiControl

AF:

0.00160

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Upshaw-Schulman syndrome

Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 10, 2018	Across a selection of available literature, the c.3178C>T (p.Arg1060Trp) missense variant has been identified in at least five individuals in a homozygous state, five individuals in a compound heterozygous state, and five individuals in a heterozygous state, all affected with congenital or adult-onset familial thrombotic thrombocytopenia purpura (TTP) (Schneppenheim et al. 2006; Tao et al. 2006; Camilleri et al. 2008; Lotta et al. 2012). Camilleri et al. (2008) showed the variant segregated with disease in one family. The p.Arg1060Trp variant was absent from at least 199 healthy control subjects but is reported at a frequency of 0.002982 in the European population of the 1000 Genomes Project (Tao et al. 2006; Lotta et al. 2012). In vitro analysis of the p. Arg1060Trp variant in HEK293T and Hela cells exhibited significantly reduced enzyme activity ranging from less than 5% to 11.4% of wild type enzyme activity (Schneppenheim et al. 2006; Tao et al. 2006; Camilleri et al. 2008; Lotta et al. 2012). In vitro flow assay evaluating cleavage under normal and static flow conditions found the p.Arg1060Trp variant had significantly reduced cleavage under static conditions but normal cleavage under normal flow conditions (Tao et al. 2006). Based on the evidence the p.Arg1060Trp variant is considered to be pathogenic for familial thrombotic thrombocytopenia purpura. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	Jan 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Versiti Diagnostic Laboratories, Versiti, Inc	Apr 10, 2024	The missense variant ADAMTS13 c.3178C>T, p.Arg1060Trp (p.R1060W) in exon 24 changes amino acid arginine at codon 1060 to tryptophan. The arginine at this residue is moderately conserved among species. This amino acid is in a C-terminal TSP1 repeat, a region thought to inhibit platelet adhesion and aggregation or thrombus formation. Pathogenic variants in ADAMTS13 are associated with autosomal recessive congenital ADAMTS13 deficiency (also known as familial/inherited thrombotic thrombocytopenic purpura (TTP) and Upshaw-Schulman syndrome) characterized by increased risk of life-threatening thrombotic microangiopathy (thrombocytopenia, microangiopathic hemolytic anemia, microvascular thrombosis and organ dysfunction). This sequence variant has been previously reported in multiple patients and families with adult onset thrombotic thrombocytopenic purpura (TTP) (PMID:16807643; PMID:16796708; PMID:18031293). This variant was observed in 30 patients within our laboratory cohort; 3 patients were homozygous for this variant while 22 patients were compound heterozygotes for this variant and another ADAMTS13 variant classified by our laboratory as likely pathogenic (LP) or pathogenic (P). All 3 patients who were homozygous for this particular variant had a documented ADAMTS13 activity of <5% with negative inhibitor and undetectable antibody. Of the 22 patients who were compound heterozygotes for this variant and another LP/P variant, we received ADAMTS13 activity level and inhibitor status for 17; 16 of these 17 patients had a documented ADAMTS13 activity level of <10% with negative inhibitor. The minor allele frequency of this variant in the general population is 0.0008318 with an elevated allele frequency of 0.001309 in the European (non-Finnish) population (GnomAD v2). Functional studies of the variant in mammalian cells demonstrated that this variant causes severe intracellular retention (<5% secretion) of the ADAMTS13 protein (PMID:18031293). In summary, the collective evidence supports ADAMTS13 c.3178C>T, p.Arg1060Trp as a pathogenic variant for congenital ADAMTS13 deficiency. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 20, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Mar 24, 2024	The ADAMTS13:c.3178C>T (p.Arg1060Trp) variant has been reported in individuals affected with congenital thrombotic thrombocytopenic purpura, a condition that can manifest in adult hood during pregnancy (Mariotte E et al., PMID: 27132698; de Vries PS et al., PMID: 25934476; Scully M et al., PMID: 24859360; Camilleri RS et al., PMID: 18031293; Joly BS et al., PMID: 30312976; Alwan F et al., PMID: 30770395; Moatti-Cohen M et al., PMID: 22547583, Donadelli et al., PMID: 17003922). The ADAMTS13:c.3178C>T (p.Arg1060Trp) variant has been reported in the ClinVar database as pathogenic/likely pathogenic by 14 submitters (Variation ID: 68815). Computational predictors are uncertain as to the impact of this variant on ADAMTS13 function. Functional in vitro studies show that this variant causes intracellular retention and impaired synthesis of ADAMTS13, indicating that this variant impacts protein function (Camilleri RS et al., PMID: 18031293; Tao Z et al., PMID: 16796708; Joly BS et al., PMID: 30312976, Donadelli et al., PMID: 17003922). Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 13, 2021	PS3, PP1, PP3, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 08, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with thrombotic thrombocytopenic purpura, hereditary (MIM#274150). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 124 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 37 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Thrombospondin type 1 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and is one of the most common variants reported in individuals with Thrombotic Thrombocytopenic Purpura (ClinVar, PMID: 18031293, 30792199). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies showed this variant causes severe intracellular retention (<5% secretion) of ADAMTS-13 (PMID: 18031293). (SP) 1101 - Very strong and specific phenotype match for this individual. She has been reported to have reduced ADAMTS13 activity (personal communications). (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (c.725G>A; p.(Cys242Tyr)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 05, 2024	PP1, PM1_supporting, PM3, PS3, PS4_moderate -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	Published functional studies demonstrate intracellular retention (Camilleri et al., 2008; Hassenpflug et al., 2018); This variant is associated with the following publications: (PMID: 31980526, 22529288, 23346910, 29554699, 18031293, 31971692, 30792199, 25934476, 16807643, 16796708, 26352112, 26139087) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1060 of the ADAMTS13 protein (p.Arg1060Trp). This variant is present in population databases (rs142572218, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with late-onset and/or pregnancy-related thrombotic thrombocytopenic purpura (PMID: 16796708, 16807643, 17003922, 18031293, 22547583, 26352112, 29554699, 30792199). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68815). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ADAMTS13 function (PMID: 18031293). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 30, 2022	- -

Thrombotic thrombocytopenic purpura

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 15, 2022

Variant summary: ADAMTS13 c.3178C>T (p.Arg1060Trp) results in a non-conservative amino acid change located in the Thrombospondin type-1 (TSP1) repeat (IPR000884) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 245122 control chromosomes (gnomAD). c.3178C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Thrombotic Thrombocytopenic Purpura (e.g. Donadelli_2006, Tao_2006, Camilleri_2008, Scully_2014, Hassenpflug_2018, van Dorland_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant results in reduced protein secretion and activity (e.g. Tao_2006, Camilleri_2008, Rurali_2015, Hassenpflug_2018, van Dorland_2019). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

ADAMTS13-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2024

The ADAMTS13 c.3178C>T variant is predicted to result in the amino acid substitution p.Arg1060Trp. This variant has been reported in the homozygous and compound heterozygous states in multiple patients with adult-onset thrombotic thrombocytopenic purpura (TTP) (Tao et al. 2006. PubMed ID: 16796708; Patient 5 in Schneppenheim et al. 2006. PubMed ID: 16807643; Enjeti et al. 2015. PubMed ID: 26352112) and pregnancy-related TTP (Family 226 in Donadelli et al. 2006. PubMed ID: 17003922; Scully et al. 2014. PubMed ID: 24859360; Rurali et al. 2015. PubMed ID: 26342041). It has been noted that women with this variant often present with TTP during their first pregnancy, while men with this variant often remain asymptomatic until later in life (Delmas et al. 2020. PubMed ID: 31971692). Functional analysis showed that this variant had variable metalloprotease activity ranging from normal (Camilleri et al. 2009. PubMed ID: 18031293) to reduced function (~46% of wild type activity) (Rurali et al. 2015. PubMed ID: 26342041; Hassenpflug et al. 2018. PubMed ID: 29554699). Additional studies showed an increase in intracellular retention (Camilleri et al. 2009. PubMed ID: 18031293; Rurali et al. 2015. PubMed ID: 26342041; Hassenpflug et al. 2018. PubMed ID: 29554699). This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Based on this evidence, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.066

T;T;T

MetaSVM

Uncertain

-0.019

MutationAssessor

Uncertain

2.9

M;M;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-6.1

D;D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

1.0

D;D;D

Vest4

0.41

MVP

0.90

MPC

1.1

ClinPred

0.095

GERP RS

3.2

Varity_R

0.12

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over