ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.275C>T (p.Thr92Met)

gnomAD frequency: 0.00001  dbSNP: rs751010538
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000677535 SCV000803046 uncertain significance Mucopolysaccharidosis type 6 2018-01-01 criteria provided, single submitter curation Very low frequency in GnomAD (PM2)
Labcorp Genetics (formerly Invitae), Labcorp RCV000677535 SCV003256312 likely pathogenic Mucopolysaccharidosis type 6 2024-05-29 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 92 of the ARSB protein (p.Thr92Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type VI (PMID: 8651289, 22976768). ClinVar contains an entry for this variant (Variation ID: 559759). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSB protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSB function (PMID: 8651289). This variant disrupts the p.Thr92 amino acid residue in ARSB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17458871, 30982216). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Fulgent Genetics, Fulgent Genetics RCV000677535 SCV005673128 likely pathogenic Mucopolysaccharidosis type 6 2024-06-21 criteria provided, single submitter clinical testing

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