ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.817G>A (p.Asp273Asn) (rs1046551417)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668913 SCV000793588 uncertain significance Mucopolysaccharidosis, MPS-III-A 2017-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781846 SCV000920208 uncertain significance not specified 2019-07-22 criteria provided, single submitter clinical testing Variant summary: SGSH c.817G>A (p.Asp273Asn) results in a conservative amino acid change located in the sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four 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 250174 control chromosomes (gnomAD) and been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Beesley_2000, Truxal_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, based on the atomic structure of SGSH, Sidhu et. al. report that this variant may disrupts Ca2+ binding (Sidhu_2013). One other submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000668913 SCV000947471 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-01-04 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 273 of the SGSH protein (p.Asp273Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another SGSH variant in individuals affected with mucopolysaccharidosis type III (PMID: 11182930, 27590925, Invitae). ClinVar contains an entry for this variant (Variation ID: 553454). 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 C15"). For these reasons, this variant has been classified as Pathogenic.

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