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

gnomAD frequency: 0.00002  dbSNP: rs121918185

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000170582	SCV000222678	likely pathogenic	Non-immune hydrops fetalis	2014-11-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000956	SCV000831492	pathogenic	Mucopolysaccharidosis type 7	2023-11-22	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. Loss-of-function variants in GUSB are known to be pathogenic (PMID: 19224584). This variant is present in population databases (rs121918185, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis VII (PMID: 7680524, 19224584). ClinVar contains an entry for this variant (Variation ID: 908). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, 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.
GeneDx	RCV001528837	SCV002765177	pathogenic	not provided	2022-12-13	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 29620724, 7680524, 26036949, 34645488)
Fulgent Genetics, Fulgent Genetics	RCV000000956	SCV002781237	pathogenic	Mucopolysaccharidosis type 7	2022-03-14	criteria provided, single submitter	clinical testing
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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528837	SCV001964617	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528837	SCV002037473	pathogenic	not provided		no assertion criteria provided	clinical testing