ClinVar Miner

Submissions for variant NM_000181.4(GUSB):c.1069C>T (p.Arg357Ter) (rs121918185)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000170582 SCV000222678 likely pathogenic Non-immune hydrops fetalis 2014-11-01 criteria provided, single submitter research
Invitae RCV000000956 SCV000831492 pathogenic Mucopolysaccharidosis type 7 2017-09-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg357*) in the GUSB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121918185, ExAC 0.003%). This variant has been reported in individuals affected with mucopolysaccharidosis VII (PMID: 7680524, 19224584). ClinVar contains an entry for this variant (Variation ID: 908). Loss-of-function variants in GUSB are known to be pathogenic (PMID: 19224584). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000000956 SCV000916202 pathogenic Mucopolysaccharidosis type 7 2017-04-28 criteria provided, single submitter clinical testing The GUSB c.1069C>T (p.Arg357Ter) variant is a stop-gained variant that has been reported in at least five studies where it is found in a total of nine individuals with mucopolysaccharidosis, type VII, including four in a homozygous state and five in a compound heterozygous state (Shipley et al. 1993; Vervoort et al. 1995; Vervoort et al. 1996; Vervoort et al. 1997; Shamseldin et al. 2015). Three of the homozygous individuals are related, representing a parent and two prenatally diagnosed fetuses. The p.Arg357Ter variant was found to segregate with disease in at least one family (Shipley et al. 1993). Control data are unavailable for this variant, which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on two alleles in a region of good sequencing coverage so the variant is presumed to be rare. Expression of the p.Arg357Ter variant in COS-7 cells resulted in no enzyme activity and analysis of total RNA from cultured fibroblasts revealed reduced amounts of variant mRNA and aberrant bands suggesting aberrant splicing (Shipley et al. 1993; Vervoort et al. 1996). Based on the evidence and the potential impact of stop-gained variants, the p.Arg357Ter variant is classified as pathogenic for mucopolysaccharidosis, type VII. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000000956 SCV001251541 likely pathogenic Mucopolysaccharidosis type 7 criteria provided, single submitter research The GUSB c.1069C>T (p.R357*) nonsense variant is predicted to result in nonsense-mediated decay and/or premature termination of the GUSB protein. This variant has been reported in multiple individuals with mucopolysaccharidosis VII (PMID: 7680524; 8644704; 19224584).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000956 SCV001426986 pathogenic Mucopolysaccharidosis type 7 2020-07-20 criteria provided, single submitter clinical testing Variant summary: GUSB c.1069C>T (p.Arg357X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 251312 control chromosomes. c.1069C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type VII or related disease (Vervoort_1996, Maddirevula_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing that p.Arg357X affects the normal gene function (Vervoort_1996). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Bothlaboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000956 SCV000021106 pathogenic Mucopolysaccharidosis type 7 1993-03-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001528837 SCV001741259 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.