Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis VII (MIM#253220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR studies have shown that this variant creates a cryptic donor splice site that leads to two abnormal splicing outcomes - partial skipping of exon 10 and complete skipping of exon 9. Both of these abnormal splicing events cause out of frame deletions and NMD-predicted frameshifts, p.(Ser539Argfs*8) for partial exon 10 skipping and p.(Met465Leufs*6) for exon 9 skipping (PMIDs: 30442200, 7633414). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, PMID: 19224584). (SP) 0803 - This variant has limited previous evidence of pathogenicity in two unrelated individuals. This variant has been observed as compound heterozygous in one individual and as homozygous in another with mucopolysaccharidosis (PMIDs: 30442200, 7633414). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in fibroblasts found variant protein had significantly reduced enzyme activity compared to wild type protein (PMID: 7633414). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ClinVar Genomic variation as it relates to human health
NM_000181.4(GUSB):c.1617C>T (p.Ser539=)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(4)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000181.4(GUSB):c.1617C>T (p.Ser539=)
Variation ID: 901 Accession: VCV000000901.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.21 7: 65967767 (GRCh38) [ NCBI UCSC ] 7: 65432754 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 12, 2015 Feb 28, 2024 Jan 18, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000181.4:c.1617C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000172.2:p.Ser539= synonymous NM_001284290.2:c.1179C>T NP_001271219.1:p.Ser393= synonymous NM_001293104.2:c.1047C>T NP_001280033.1:p.Ser349= synonymous NM_001293105.2:c.960C>T NP_001280034.1:p.Ser320= synonymous NR_120531.2:n.1562C>T non-coding transcript variant NC_000007.14:g.65967767G>A NC_000007.13:g.65432754G>A NG_016197.1:g.19548C>T NP_000172.2:p.Ser539Argfs*8 - Protein change
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- Other names
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- Canonical SPDI
- NC_000007.14:65967766:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
- Comment on variant
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GUSB | - | - |
GRCh38 GRCh37 |
609 | 668 | |
| LOC126860055 | - | - | - | GRCh38 | - | 48 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 18, 2024 | RCV000000949.12 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type 7
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768930.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis VII (MIM#253220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR studies have shown that this variant creates a cryptic donor splice site that leads to two abnormal splicing outcomes - partial skipping of exon 10 and complete skipping of exon 9. Both of these abnormal splicing events cause out of frame deletions and NMD-predicted frameshifts, p.(Ser539Argfs*8) for partial exon 10 skipping and p.(Met465Leufs*6) for exon 9 skipping (PMIDs: 30442200, 7633414). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, PMID: 19224584). (SP) 0803 - This variant has limited previous evidence of pathogenicity in two unrelated individuals. This variant has been observed as compound heterozygous in one individual and as homozygous in another with mucopolysaccharidosis (PMIDs: 30442200, 7633414). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in fibroblasts found variant protein had significantly reduced enzyme activity compared to wild type protein (PMID: 7633414). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Aug 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type 7
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002785612.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type 7
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002243058.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects codon 539 of the GUSB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 539 of the GUSB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GUSB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs377519272, gnomAD 0.008%). This variant has been observed in individual(s) with mucopolysaccharidosis (MPS) VII (PMID: 7633414, 30442200). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 901). Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID: 7633414, 30442200). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 01, 1995)
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no assertion criteria provided
Method: literature only
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MUCOPOLYSACCHARIDOSIS, TYPE VII
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021099.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2015 |
Comment on evidence:
In a Caucasian patient with a severe form of mucopolysaccharidosis type VII (MPS7; 253220), Yamada et al. (1995) identified compound heterozygosity for 2 mutations in … (more)
In a Caucasian patient with a severe form of mucopolysaccharidosis type VII (MPS7; 253220), Yamada et al. (1995) identified compound heterozygosity for 2 mutations in the GUSB gene: a 38-bp deletion at position 1642-1679 in exon 10 (1642del38nt), and W507X (611499.0008). The deletion was caused by a C-to-T transition in exon 10, which together with the previous guanine, created the GT of a new, premature 5-prime splice site. Functional expression studies showed that the mutant proteins had severely decreased enzyme activity. (less)
|
Comment:
Comment:
This sequence change affects codon 539 of the GUSB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GUSB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs377519272, gnomAD 0.008%). This variant has been observed in individual(s) with mucopolysaccharidosis (MPS) VII (PMID: 7633414, 30442200). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 901). Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID: 7633414, 30442200). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis VII (MIM#253220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR studies have shown that this variant creates a cryptic donor splice site that leads to two abnormal splicing outcomes - partial skipping of exon 10 and complete skipping of exon 9. Both of these abnormal splicing events cause out of frame deletions and NMD-predicted frameshifts, p.(Ser539Argfs*8) for partial exon 10 skipping and p.(Met465Leufs*6) for exon 9 skipping (PMIDs: 30442200, 7633414). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, PMID: 19224584). (SP) 0803 - This variant has limited previous evidence of pathogenicity in two unrelated individuals. This variant has been observed as compound heterozygous in one individual and as homozygous in another with mucopolysaccharidosis (PMIDs: 30442200, 7633414). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in fibroblasts found variant protein had significantly reduced enzyme activity compared to wild type protein (PMID: 7633414). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This sequence change affects codon 539 of the GUSB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GUSB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs377519272, gnomAD 0.008%). This variant has been observed in individual(s) with mucopolysaccharidosis (MPS) VII (PMID: 7633414, 30442200). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 901). Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID: 7633414, 30442200). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A new case report of severe mucopolysaccharidosis type VII: diagnosis, treatment with haematopoietic cell transplantation and prenatal diagnosis in a second pregnancy. | Furlan F | Italian journal of pediatrics | 2018 | PMID: 30442200 |
| Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome). | Tomatsu S | Human mutation | 2009 | PMID: 19224584 |
| Four novel mutations in mucopolysaccharidosis type VII including a unique base substitution in exon 10 of the beta-glucuronidase gene that creates a novel 5'-splice site. | Yamada S | Human molecular genetics | 1995 | PMID: 7633414 |
Text-mined citations for rs377519272 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
This variant is not a genomic deletion; it is a single nucleotide variant in exon 10 that converts a GC to a GT, resulting in a premature splice donor site that causes a 32-nt frame-shifting deletion in the transcript.