ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.544C>T (p.Arg182Cys) (rs529855742)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000626217 SCV000746862 pathogenic Mucopolysaccharidosis, MPS-III-A 2017-12-18 criteria provided, single submitter clinical testing
Center for Medical Genetics,GenVams Trust RCV000626217 SCV000897637 pathogenic Mucopolysaccharidosis, MPS-III-A criteria provided, single submitter clinical testing The Arg182Cys variant in SGSH has been reported in a hetoroallelic Italian patient. In the patient, the variant caused absence of restriction site of MspA11 enzyme. This cleaved the 296 bp segment to 200 and 96 bp segments. This study also noted the phenotype to be intermediate in terms of severity (di Natale et al, 1998). However, our patient, being homozygous for the Arg182Cs variant, showed intermediate-severe phenotype. The Arg182Cys variant has not been reported in the testing organization's (secondary organization here) internal database and has a minor allele frequency of 0.02% and 0.0008% in the 1000 genomes and ExAC databases respectively. The in silico prediction of the variant is probably damaging by PolyPhen-2 (HumDiv) and damaging by LRT, SIFT and MutationTaster2.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000626217 SCV000929897 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2019-01-01 criteria provided, single submitter literature only PS3: Low in vitro enzymatic activity. PM2: Very low frequency in ExAc
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000626217 SCV002015190 pathogenic Mucopolysaccharidosis, MPS-III-A 2021-10-06 criteria provided, single submitter clinical testing Variant summary: SGSH c.544C>T (p.Arg182Cys) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) 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 1.2e-05 in 244306 control chromosomes. c.544C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (example, Di Natale_1998, Valstar_2010, Heron_2011, Zanetti_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal Sulfamidase enzyme activity in a homozygous patient (example, Zanetti_2019). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Nilou-Genome Lab RCV000626217 SCV002045502 pathogenic Mucopolysaccharidosis, MPS-III-A 2021-11-07 criteria provided, single submitter clinical testing

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