ClinVar Miner

Submissions for variant NM_000181.4(GUSB):c.526C>T (p.Leu176Phe) (rs121918181)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000000953 SCV001582514 pathogenic Mucopolysaccharidosis type 7 2020-02-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 176 of the GUSB protein (p.Leu176Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs121918181, ExAC 0.01%). This variant has been observed in individual(s) with mucopolysaccharidosis VII (PMID: 7573038, 19224584, 8644704, 8089138, 12859417). It has also been observed to segregate with disease in related individuals. This variant is also known as 552C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 905). This variant has been reported to affect GUSB protein function (PMID: 8089138, 12403825). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000953 SCV000021103 pathogenic Mucopolysaccharidosis type 7 2003-08-01 no assertion criteria provided literature only

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