ClinVar Miner

Submissions for variant NM_139027.6(ADAMTS13):c.3284G>A (p.Arg1095Gln)

gnomAD frequency: 0.00001  dbSNP: rs373569027
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV001358530 SCV004226829 pathogenic not provided 2022-02-11 criteria provided, single submitter clinical testing PP3, PP4, PM1, PM2_supporting, PM3_strong, PS3_moderate
Fulgent Genetics, Fulgent Genetics RCV005040211 SCV005678077 uncertain significance Upshaw-Schulman syndrome 2024-02-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001358530 SCV001554291 likely pathogenic not provided no assertion criteria provided clinical testing The ADAMTS13 p.R1095Q variant was identified in the compound heterozygous state in 1/18 patients with congenital thrombotic thrombocytopenic purpura (TTP) and funcitonal studies of this variant demonstrated impaired protein function compared to wildtype (Rurali_2015_PMID:26342041). The variant was also identified in 1/6 patients with adult‚Äêonset TTP precipitated by pregnancy; the patient with the R1095Q variant also had non‚Äêpregnancy‚Äêassociated TTP episodes (Camilleri_2012_PMID:22783805). The variant was identified in dbSNP (ID: rs373569027) but was not identified in ClinVar, Clinvitae, Cosmic or LOVD 3.0. The variant was identified in the NHLBI GO Exome Sequencing Project database in 1 of 13006 chromosomes (freq=0.000077) but was not found in the 1000 Genomes Project, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Arg1095 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. However, a functional study assessing ADAMTS13 activity and genetic mutations in a Japanese population demonstrated decreased ADAMTS13 activity from the R1095Q variant compared to wildtype (Miyata_2013_PMID:23715102). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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