ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.449G>A (p.Arg150Gln) (rs104894638)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000005420 SCV000798966 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2018-04-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000005420 SCV000920207 pathogenic Mucopolysaccharidosis, MPS-III-A 2018-10-04 criteria provided, single submitter clinical testing Variant summary: SGSH c.449G>A (p.Arg150Gln) results in a conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276994 control chromosomes (gnomAD and publication data). c.449G>A has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Bunge 1997, Di Natale 1998, Heron 2010, Valstar 2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on enzyme activity, showing that the variant results in <10% of normal activity (Esposito 2000). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000005420 SCV000754682 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2018-01-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 150 of the SGSH protein (p.Arg150Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs104894638, ExAC 0.01%). This variant has been reported as homozygous or in combination with another SGSH variant in individuals affected with mucopolysaccharidosis type III (PMID: 9401012, 9554748, 9744479, 21204211). ClinVar contains an entry for this variant (Variation ID: 5113). Experimental studies have shown that this missense change abrogates SGSH enzyme activity (PMID: 10727844). 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.
OMIM RCV000005420 SCV000025602 pathogenic Mucopolysaccharidosis, MPS-III-A 1998-01-01 no assertion criteria provided literature only

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