ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000005420 SCV000754682 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-08-29 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, 11343308, 21061399). ClinVar contains an entry for this variant (Variation ID: 5113). Experimental studies have shown that this missense change abrogates SGSH enzyme activity (PMID: 10727844). This variant disrupts the p.Arg150 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 11182930, 21204211), which suggests that this may be a clinically significant amino acid residue. For these reasons, this allele has been classified as Pathogenic.
Counsyl RCV000005420 SCV000798966 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2018-04-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Nilou-Genome Lab RCV000005420 SCV002045504 pathogenic Mucopolysaccharidosis, MPS-III-A 2021-11-07 criteria provided, single submitter clinical testing
OMIM RCV000005420 SCV000025602 pathogenic Mucopolysaccharidosis, MPS-III-A 1998-01-01 no assertion criteria provided literature only
PerkinElmer Genomics RCV000005420 SCV002019209 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2020-12-28 no assertion criteria provided clinical testing

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