Submissions for variant NM_000046.5(ARSB):c.215T>C (p.Leu72Pro)

gnomAD frequency: 0.00003  dbSNP: rs397514441

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000677515	SCV000803025	uncertain significance	Mucopolysaccharidosis type 6	2018-01-01	criteria provided, single submitter	curation	Very low frequency in GnomAD (PM2)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000677515	SCV002132557	pathogenic	Mucopolysaccharidosis type 6	2021-10-15	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 559739). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 24373060). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 72 of the ARSB protein (p.Leu72Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu72 amino acid residue in ARSB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16435196, 17458871, 25190157; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.