ClinVar Genomic variation as it relates to human health
NM_000181.4(GUSB):c.526C>T (p.Leu176Phe)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000181.4(GUSB):c.526C>T (p.Leu176Phe)
Variation ID: 905 Accession: VCV000000905.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.21 7: 65979782 (GRCh38) [ NCBI UCSC ] 7: 65444769 (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 Aug 22, 2016 Mar 16, 2024 Dec 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000181.4:c.526C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000172.2:p.Leu176Phe missense NM_001284290.2:c.474+52C>T intron variant NM_001293104.2:c.12-241C>T intron variant NM_001293105.2:c.67+442C>T intron variant NR_120531.2:n.556C>T non-coding transcript variant NC_000007.14:g.65979782G>A NC_000007.13:g.65444769G>A NG_016197.1:g.7533C>T P08236:p.Leu176Phe - Protein change
- L176F
- Other names
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- Canonical SPDI
- NC_000007.14:65979781: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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GUSB | - | - |
GRCh38 GRCh37 |
592 | 651 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 9, 2023 | RCV000000953.30 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2019 | RCV000586449.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 5, 2023 | RCV000790722.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV003914794.1 |
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
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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
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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
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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
(Nov 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000228805.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 8
Sex: mixed
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Pathogenic
(Aug 16, 2019)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type VI
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695938.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 08, 2019 |
Comment:
Variant summary: GUSB c.526C>T (p.Leu176Phe) results in a non-conservative amino acid change located in the Glycosyl hydrolases family 2, sugar binding domain (IPR006104) of the … (more)
Variant summary: GUSB c.526C>T (p.Leu176Phe) results in a non-conservative amino acid change located in the Glycosyl hydrolases family 2, sugar binding domain (IPR006104) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250940 control chromosomes (gnomAD). c.526C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type VII (Sly Syndrome) (Wu_1994, Vervoort_1996, Schwartz_2003, Montano_2016). These data indicate that the variant is very likely to be associated with disease. Functional studies found the variant to have <10% of normal activity (Wu_1994, Puxan_2018). In addition, a knock-in mouse model with the L175F mutation, corresponding to the L176F variant in humans, exhibited phenotypic characteristics typical of Mucopolysaccharidosis Type VII (Tomatsu_2002). A ClinVar submission (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type 7
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002099087.1 First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022 |
Clinical Features:
Seizure (present) , Intellectual disability (present) , Autism (present)
Secondary finding: no
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Pathogenic
(Jan 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type 7
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV003843196.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
This variant was observed in compound heterozygosity with variant c.1145G>A
Method: Exome sequencing
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Pathogenic
(May 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type 7
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024930.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 07, 2021)
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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: SCV000894434.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002819012.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Published functional studies demonstrate a damaging effect (Tomatsu et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); Reported as the most … (more)
Published functional studies demonstrate a damaging effect (Tomatsu et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); Reported as the most common variant among patients with MPS VII (Tomatsu et al., 2009); This variant is associated with the following publications: (PMID: 7573038, 8089138, 31980526, 34022924, 31589614, 12859417, 8644704, 19224584, 12403825) (less)
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Pathogenic
(Dec 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type 7
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001582514.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 176 of the GUSB protein (p.Leu176Phe). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 176 of the GUSB protein (p.Leu176Phe). This variant is present in population databases (rs121918181, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis VII (PMID: 7573038, 8089138, 8644704, 12859417, 19224584). It has also been observed to segregate with disease in related individuals. This variant is also known as 552C>T. ClinVar contains an entry for this variant (Variation ID: 905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GUSB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GUSB function (PMID: 8089138, 12403825). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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GUSB-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004741983.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The GUSB c.526C>T variant is predicted to result in the amino acid substitution p.Leu176Phe. This variant has been reported to be causative for mucopolysaccharidosis type … (more)
The GUSB c.526C>T variant is predicted to result in the amino acid substitution p.Leu176Phe. This variant has been reported to be causative for mucopolysaccharidosis type VII (Vervoort et al. 1995. PubMed ID: 7573038; Vervoort et al. 1996. PubMed ID: 8644704; Tomatsu et al. 2009. PubMed ID: 19224584; Wu et al. 1994 PubMed ID: 8089138; Bayo-Puxan et al. 2018. PMID: 30413728; Schwartz et al. 2003 PMID: 12859417). Cultured fibroblasts derived from patients homozygous for this variant showed that this variant has about 2% of normal beta-glucuronidase activity (Bayo-Puxan et al. 2018. PMID: 30413728; Tomatsu et al. 2009. PubMed ID: 19224584). The mouse model of homozygous p.Leu176Phe had low level of residual enzymatic activity and a milder phenotype (Tomatsu et al. 2002. PubMed ID: 12403825). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. In summary, we interpret this variant as pathogenic. (less)
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Pathogenic
(Aug 01, 2003)
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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
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OMIM
Accession: SCV000021103.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a child with mucopolysaccharidosis type VII (MPS7; 253220), Vervoort et al. (1995) identified a homozygous 552C-T transition in exon 3 of the GUSB gene, … (more)
In a child with mucopolysaccharidosis type VII (MPS7; 253220), Vervoort et al. (1995) identified a homozygous 552C-T transition in exon 3 of the GUSB gene, resulting in a leu176-to-phe (L176F) substitution. Tomatsu et al. (2002) stated that the L176F mutation, which was first identified in affected members of a Mennonite family with MPS7 (Wu et al., 1994) and later observed in other populations, accounts for approximately 20% of mutant alleles of the GUSB gene. Most patients homozygous for L176F have a mild phenotype. Cells from L176F patients have less than 1% of normal GUSB activity, but expression of the L176F cDNA in COS cells produces nearly as much enzyme activity as the wildtype control cDNA. Tomatsu et al. (2002) used targeted mutagenesis to produce an L175F mutation in the mouse Gusb gene. The mutant mice had low levels of residual enzyme activity and a milder phenotype than did knockout mice with a glu536-to-ala (E536A) mutation corresponding to E540A in human MPS7. Schwartz et al. (2003) identified homozygosity for the L176F mutation in a Brazilian family in which 3 brothers were affected with MPS7. Although the 3 brothers had early onset of symptoms with peripheral edema at birth and prolonged neonatal jaundice, the evolution of the disorder in 1 of the brothers, who was still alive at age 18 years and attending a special school, suggested the intermediate form of MPS7. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Patient with anomalous skin pigmentation expands the phenotype of ARID2 loss-of-function disorder, a SWI/SNF-related intellectual disability. | Khazanchi R | American journal of medical genetics. Part A | 2019 | PMID: 30838730 |
Extending the clinical and genetic spectrum of ARID2 related intellectual disability. A case series of 7 patients. | Gazdagh G | European journal of medical genetics | 2019 | PMID: 29698805 |
Lysosomal and network alterations in human mucopolysaccharidosis type VII iPSC-derived neurons. | Bayó-Puxan N | Scientific reports | 2018 | PMID: 30413728 |
Confirmation of an ARID2 defect in SWI/SNF-related intellectual disability. | Van Paemel R | American journal of medical genetics. Part A | 2017 | PMID: 28884947 |
Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype. | Bramswig NC | Human genetics | 2017 | PMID: 28124119 |
Clinical course of sly syndrome (mucopolysaccharidosis type VII). | Montaño AM | Journal of medical genetics | 2016 | PMID: 26908836 |
Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome). | Tomatsu S | Human mutation | 2009 | PMID: 19224584 |
Mucopolysaccharidosis VII: clinical, biochemical and molecular investigation of a Brazilian family. | Schwartz I | Clinical genetics | 2003 | PMID: 12859417 |
Missense models [Gustm(E536A)Sly, Gustm(E536Q)Sly, and Gustm(L175F)Sly] of murine mucopolysaccharidosis type VII produced by targeted mutagenesis. | Tomatsu S | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 12403825 |
Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII. | Vervoort R | American journal of human genetics | 1996 | PMID: 8644704 |
A pseudodeficiency allele (D152N) of the human beta-glucuronidase gene. | Vervoort R | American journal of human genetics | 1995 | PMID: 7573038 |
Overexpression rescues the mutant phenotype of L176F mutation causing beta-glucuronidase deficiency mucopolysaccharidosis in two Mennonite siblings. | Wu BM | The Journal of biological chemistry | 1994 | PMID: 8089138 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GUSB | - | - | - | - |
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Text-mined citations for rs121918181 ...
HelpRecord last updated Apr 20, 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.