ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.221G>A (p.Arg74His)

dbSNP: rs778336949
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665263 SCV000789354 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2017-01-30 criteria provided, single submitter clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000665263 SCV000929893 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2019-01-01 criteria provided, single submitter literature only PS3: Low in vitro enzymatic activity. PM2: Absent from GnomAD
Invitae RCV000665263 SCV000936017 pathogenic Mucopolysaccharidosis, MPS-III-A 2023-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 74 of the SGSH protein (p.Arg74His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with MPS IIIA (PMID: 9401012, 11343308; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550504). 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 SGSH protein function with a positive predictive value of 95%. This variant disrupts the p.Arg74 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9285796, 9401012, 11343308, 22976768, 28844463). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000665263 SCV001774435 pathogenic Mucopolysaccharidosis, MPS-III-A 2021-08-03 criteria provided, single submitter clinical testing Variant summary: SGSH c.221G>A (p.Arg74His) 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 4.7e-06 in 211504 control chromosomes (gnomAD and publication data). c.221G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A), including at least two homozygotes (Bunge_1997, Chabas_2001, Montfort_2004). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant results in reducing sulfamidase activity compared to WT activity (Montfort_2004). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000665263 SCV002045507 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2021-11-07 criteria provided, single submitter clinical testing
Baylor Genetics RCV000665263 SCV004201068 pathogenic Mucopolysaccharidosis, MPS-III-A 2023-10-24 criteria provided, single submitter clinical testing

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