Submissions for variant NM_000046.5(ARSB):c.1325C>T (p.Thr442Met) (rs1057520739)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000435336	SCV000706443	uncertain significance	not provided	2017-02-21	criteria provided, single submitter	clinical testing
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.
Invitae	RCV000632186	SCV000753291	uncertain significance	Mucopolysaccharidosis type VI	2018-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 442 of the ARSB protein (p.Thr442Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals affected with mucopolysaccharidosis type VI (PMID: 17458871, 25190157). ClinVar contains an entry for this variant (Variation ID: 379809). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova	RCV000632186	SCV000802983	uncertain significance	Mucopolysaccharidosis type VI	2018-01-01	criteria provided, single submitter	curation	Absent from GnomAD (PM2)