ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.383C>T (p.Pro128Leu)

gnomAD frequency: 0.00002  dbSNP: rs104894642
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000005417 SCV003443329 pathogenic Mucopolysaccharidosis, MPS-III-A 2024-10-28 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 128 of the SGSH protein (p.Pro128Leu). This variant is present in population databases (rs104894642, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 9554748, 12702166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5110). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SGSH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000005417 SCV004201114 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2024-03-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004766982 SCV005381564 uncertain significance not specified 2024-08-02 criteria provided, single submitter clinical testing Variant summary: SGSH c.383C>T (p.Pro128Leu) results in a non-conservative amino acid change located in the sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249978 control chromosomes. c.383C>T has been reported in the literature in the compound heterozygous state in at least one individual affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (e.g. DiNatale_1998, DiNatale_2003). These data do not allow any conclusion about variant significance. At least one in vitro study in COS cells shows that this variant results in approximately 12% activity compared to wildtype (e.g. Esposito_2000). The following publications have been ascertained in the context of this evaluation (PMID: 12702166, 9554748, 10727844). ClinVar contains an entry for this variant (Variation ID: 5110). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000005417 SCV005653292 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2024-04-06 criteria provided, single submitter clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000005417 SCV005871472 likely pathogenic Mucopolysaccharidosis, MPS-III-A criteria provided, single submitter clinical testing PM2_Supporting+PS3_Moderate+PM3_Strong
OMIM RCV000005417 SCV000025599 pathogenic Mucopolysaccharidosis, MPS-III-A 2003-04-01 no assertion criteria provided literature only

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