ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.221G>A (p.Arg74His) (rs778336949)

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Total submissions: 5
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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 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 74 of the SGSH protein (p.Arg74His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs778336949, ExAC 0.01%). This variant has been observed as homozygous, on the opposite chromosome (in trans) from other pathogenic variants, or in combination with a rare SGSH variants in several individuals affected with MPS IIIA (PMID: 9401012, 11343308, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Variants that disrupt the p.Arg74 amino acid residue in SGSH have been observed in affected individuals (PMID: 9401012, 9285796, 22976768, 28844463, 11343308). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
Nilou-Genome Lab RCV000665263 SCV002045507 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2021-11-07 criteria provided, single submitter clinical testing

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