Submissions for variant NM_000046.5(ARSB):c.275C>A (p.Thr92Lys)

dbSNP: rs751010538

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000677534	SCV003525800	pathogenic	Mucopolysaccharidosis type 6	2022-06-23	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17458871, 30982216). ClinVar contains an entry for this variant (Variation ID: 559758). 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. This variant disrupts the p.Thr92 amino acid residue in ARSB. Other variant(s) that disrupt this residue have been observed in individuals with ARSB-related conditions (PMID: 8651289, 29202552), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 92 of the ARSB protein (p.Thr92Lys).
PreventionGenetics, part of Exact Sciences	RCV003392515	SCV004110713	likely pathogenic	ARSB-related disorder	2023-09-30	criteria provided, single submitter	clinical testing	The ARSB c.275C>A variant is predicted to result in the amino acid substitution p.Thr92Lys. This variant was reported in the compound heterozygous and homozygous state in several unrelated individuals with mucopolysaccharidosis VI (Supp. Table 1 in Karageorgos et al 2007. PubMed ID: 17458871; Jafaryazdi R et al 2019. PubMed ID: 30982216). Other amino acid substitutions at this position (p.Thr92Met, p.Thr92Pro) have also been reported in patients with mucopolysaccharidosis VI (Litjens et al 1996. PubMed ID: 8651289; Abbasi et al 2017. PubMed ID: 29202552). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV000677534	SCV004209925	pathogenic	Mucopolysaccharidosis type 6	2023-02-23	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000677534	SCV000803045	uncertain significance	Mucopolysaccharidosis type 6	2018-01-01	flagged submission	curation	Absent from GnomAD (PM2); Reputable source identifies as pathogenic (PP5)