Submissions for variant NM_000046.5(ARSB):c.1325C>T (p.Thr442Met)

dbSNP: rs1057520739

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000435336	SCV000517249	pathogenic	not provided	2015-05-27	criteria provided, single submitter	clinical testing	The T442M variant in the ARSB gene has been reported previously in the compound heterozygous statein an individual with mucopolysaccharidosis type VI (MPS VI) (Karageorgos et al., 2007). The T442Msubstitution was not observed in approximately 6500 individuals of European and African American ancestryin the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The T442M variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. This substitutionoccurs at a position that is conserved across species. Missense variants in the same (T442R) and nearby(K439E, P445L, and G446R) residues have been reported in the Human Gene Mutation Database inassociation with MPS VI (Stenson et al., 2014), supporting the functional importance of this region of theprotein. We interpret T442M as a pathogenic variant.
Eurofins Ntd Llc (ga)	RCV000435336	SCV000706443	uncertain significance	not provided	2017-02-21	criteria provided, single submitter	clinical testing
Invitae	RCV000632186	SCV000753291	pathogenic	Mucopolysaccharidosis type 6	2023-04-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 379809). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type IV (PMID: 17458871, 25190157; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 442 of the ARSB protein (p.Thr442Met).
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000632186	SCV000802983	uncertain significance	Mucopolysaccharidosis type 6	2018-01-01	criteria provided, single submitter	curation	Absent from GnomAD (PM2)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000632186	SCV003928877	likely pathogenic	Mucopolysaccharidosis type 6	2023-04-24	criteria provided, single submitter	clinical testing	Variant summary: ARSB c.1325C>T (p.Thr442Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251396 control chromosomes (gnomAD). c.1325C>T has been reported in the literature in the compound heterozygous state in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome), including at least one case where it was found in trans with a pathogenic variant (e.g. Karageorgos_2007, Zheng_2014, Tomanin_2018, He_2021). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17458871, 25190157, 30118150, 33985463). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=2) or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000632186	SCV004209180	pathogenic	Mucopolysaccharidosis type 6	2023-08-24	criteria provided, single submitter	clinical testing