ClinVar Miner

Submissions for variant NM_000181.4(GUSB):c.526C>T (p.Leu176Phe)

gnomAD frequency: 0.00007  dbSNP: rs121918181
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000790722 SCV000228805 pathogenic not provided 2013-11-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586449 SCV000695938 pathogenic Mucopolysaccharidosis type 6 2019-08-16 criteria provided, single submitter clinical testing 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.
Fulgent Genetics, Fulgent Genetics RCV000000953 SCV000894434 pathogenic Mucopolysaccharidosis type 7 2021-12-07 criteria provided, single submitter clinical testing
Invitae RCV000000953 SCV001582514 pathogenic Mucopolysaccharidosis type 7 2023-12-09 criteria provided, single submitter clinical testing 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.
Revvity Omics, Revvity RCV000000953 SCV002024930 pathogenic Mucopolysaccharidosis type 7 2022-05-19 criteria provided, single submitter clinical testing
New York Genome Center RCV000000953 SCV002099087 pathogenic Mucopolysaccharidosis type 7 2021-02-19 criteria provided, single submitter clinical testing
GeneDx RCV000790722 SCV002819012 pathogenic not provided 2023-01-05 criteria provided, single submitter clinical testing 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)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000000953 SCV003843196 pathogenic Mucopolysaccharidosis type 7 2020-01-21 criteria provided, single submitter clinical testing This variant was observed in compound heterozygosity with variant c.1145G>A
PreventionGenetics, part of Exact Sciences RCV003914794 SCV004741983 pathogenic GUSB-related condition 2023-12-11 criteria provided, single submitter clinical testing 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.
OMIM RCV000000953 SCV000021103 pathogenic Mucopolysaccharidosis type 7 2003-08-01 no assertion criteria provided literature only

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