Submissions for variant NM_139027.6(ADAMTS13):c.1979G>A (p.Arg660Gln)

gnomAD frequency: 0.00003  dbSNP: rs117943654

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003399044	SCV004121773	uncertain significance	not specified	2023-10-17	criteria provided, single submitter	clinical testing	Variant summary: ADAMTS13 c.1979G>A (p.Arg660Gln) results in a conservative amino acid change located in the Spacer 1 domain (IPR010294) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251316 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1979G>A in individuals affected with Thrombotic Thrombocytopenic Purpura has been reported. Publications reported experimental evidence evaluating different substitutions at the Arg660 residue (alone and together with other substitutions), and demonstrated altered activity for these variants (PMIDs: 19880749, 20075158, 20032502, 30152919), however the Arg660Gln was not evaluated in isolation, therefore these results do not allow convincing conclusions about the variant effect. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003770405	SCV004617715	uncertain significance	not provided	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 660 of the ADAMTS13 protein (p.Arg660Gln). This variant is present in population databases (rs117943654, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ADAMTS13-related conditions. ClinVar contains an entry for this variant (Variation ID: 988138). 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 tolerated. 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.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328114	SCV001449175	uncertain significance	Atypical hemolytic-uremic syndrome	2018-04-05	no assertion criteria provided	clinical testing	This individual is heterozygous for the c.1979G>A variant in the ADAMTS13 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases to be a disease causing variant. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a low allele frequency of 0.0018% (5 out of 277,124 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) is inconclusive regarding this change; PolyPhen2 and SIFT predicts it to be likely pathogenic whereas MutationTaster predicts this variant to be benign. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines.