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

gnomAD frequency: 0.00006  dbSNP: rs137853146

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523704	SCV000617793	pathogenic	not provided	2021-11-24	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic (ClinVar Variant ID# 5502; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 10417273, 27175728, 26879370, 18973246, 26582918)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005837	SCV000699365	pathogenic	Ehlers-Danlos syndrome, dermatosparaxis type	2016-02-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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	2024-01-19	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. Loss-of-function variants in ADAMTS2 are known to be pathogenic (PMID: 10417273). This variant is present in population databases (rs137853146, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with Ehlers-Danlos syndrome, type VIIC (PMID: 10417273, 18973246). ClinVar contains an entry for this variant (Variation ID: 5502). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, 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.
Revvity Omics, Revvity	RCV000005837	SCV002022231	pathogenic	Ehlers-Danlos syndrome, dermatosparaxis type	2021-10-04	criteria provided, single submitter	clinical testing
OMIM	RCV000005837	SCV000026019	pathogenic	Ehlers-Danlos syndrome, dermatosparaxis type	1999-08-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000005837	SCV001458933	pathogenic	Ehlers-Danlos syndrome, dermatosparaxis type	2020-09-16	no assertion criteria provided	clinical testing