ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.268G>A (p.Gly90Arg) (rs774010006)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665315 SCV000789415 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2017-02-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000665315 SCV001362833 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-11-15 criteria provided, single submitter clinical testing Variant summary: SGSH c.268G>A (p.Gly90Arg) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain 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 8e-06 in 248612 control chromosomes (gnomAD). c.268G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A)(Bunge_1997, Sun_2011, Heron_2011, Chistiakov_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000665315 SCV001372574 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 90 of the SGSH protein (p.Gly90Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs774010006, ExAC 0.01%). This variant has been observed in combination with another SGSH variant in several individuals affected with mucopolysaccharidosis type III (PMID: 21204211, 21455105, 24875751). ClinVar contains an entry for this variant (Variation ID: 550542). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Nilou-Genome Lab RCV000665315 SCV002045506 pathogenic Mucopolysaccharidosis, MPS-III-A 2021-11-07 criteria provided, single submitter clinical testing

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