ClinVar Miner

Submissions for variant NM_014244.5(ADAMTS2):c.673C>T (p.Gln225Ter) (rs137853146)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523704 SCV000617793 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing The Q225X variant in the ADAMTS2 gene has been reported as a homozygous variant in six unrelated patients with EDS VIIc, currently known as dermatosparaxis Ehlers-Danlos syndrome (dEDS) (Colige et al., 1999; Bar-Yosef et al., 2008). Four of these six reported affected individuals were of Ashkenazi Jewish descent. This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. In addition, it is classified in ClinVar as a pathogenic variant by one other clinical laboratory (SCV000486991.1; Landrum et al., 2016). Other biallelic loss of function variants in the ADAMTS2 gene have been reported in Human Gene Mutation Database in association with dEDS (Stenson et al., 2014). The Q225X variant is observed in 14/65180 (0.02%) non-Finnish European alleles in the ExAC data set (Lek et al., 2016). We interpret Q225X as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000005837 SCV000699365 pathogenic Ehlers-Danlos syndrome dermatosparaxis type 2016-02-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000005837 SCV000915129 pathogenic Ehlers-Danlos syndrome dermatosparaxis type 2018-08-31 criteria provided, single submitter clinical testing The ADAMTS2 c.673C>T (p.Gln225Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The variant has been reported in a homozygous state in a total of six individuals with Ehlers-Danlos syndrome (Colige et al. 1999; Bar-Yosef et al. 2008). One of the newborn individuals exhibited multiple non-traumatic congenital skull fractures and multiple other defects related to a connective tissue abnormality (Bar-Yosef et al. 2008). Control data are unavailable for the p.Gln225Ter variant, which is reported at a frequency of 0.003053 in the Ashkenazi Jewish population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants and the available evidence, the p.Gln225Ter variant is classified as pathogenic for Ehlers-Danlos syndrome, dermatosparaxis type. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000005837 SCV000961901 pathogenic Ehlers-Danlos syndrome dermatosparaxis type 2019-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln225*) in the ADAMTS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs137853146, ExAC 0.02%). This variant has been observed in several individuals affected with Ehlers-Danlos syndrome, type VIIC (PMID: 10417273, 18973246). ClinVar contains an entry for this variant (Variation ID: 5502). Loss-of-function variants in ADAMTS2 are known to be pathogenic (PMID: 10417273). For these reasons, this variant has been classified as Pathogenic.
Myriad Women's Health, Inc. RCV000005837 SCV001193904 pathogenic Ehlers-Danlos syndrome dermatosparaxis type 2020-01-03 criteria provided, single submitter clinical testing NM_014244.4(ADAMTS2):c.673C>T(Q225*) is classified as pathogenic in the context of type VIIC Ehlers-Danlos syndrome. Sources cited for classification include the following: PMID 10417273. Classification of NM_014244.4(ADAMTS2):c.673C>T(Q225*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000005837 SCV000026019 pathogenic Ehlers-Danlos syndrome dermatosparaxis type 1999-08-01 no assertion criteria provided literature only

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