ClinVar Miner

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

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Total submissions: 3
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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 2018-08-20 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.

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