rs121918185
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000181.4(GUSB):c.1069C>T(p.Arg357Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000198 in 1,612,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )
Consequence
GUSB
NM_000181.4 stop_gained
NM_000181.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 6.31
Genes affected
GUSB (HGNC:4696): (glucuronidase beta) This gene encodes a hydrolase that degrades glycosaminoglycans, including heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate. The enzyme forms a homotetramer that is localized to the lysosome. Mutations in this gene result in mucopolysaccharidosis type VII. Alternative splicing results in multiple transcript variants. There are many pseudogenes of this locus in the human genome.[provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-65974701-G-A is Pathogenic according to our data. Variant chr7-65974701-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-65974701-G-A is described in Lovd as [Pathogenic]. Variant chr7-65974701-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GUSB | NM_000181.4 | c.1069C>T | p.Arg357Ter | stop_gained | 7/12 | ENST00000304895.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GUSB | ENST00000304895.9 | c.1069C>T | p.Arg357Ter | stop_gained | 7/12 | 1 | NM_000181.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251312Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135860
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GnomAD4 exome AF: 0.0000199 AC: 29AN: 1460442Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14AN XY: 726556
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis type 7 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 14, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 20, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | 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). - |
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2022 | 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) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Non-immune hydrops fetalis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Nov 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at