Submissions for variant NM_000046.5(ARSB):c.1197C>G (p.Phe399Leu)

dbSNP: rs200793396

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000677462	SCV000802969	likely pathogenic	Mucopolysaccharidosis type 6	2018-01-01	criteria provided, single submitter	curation	In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAC (PM2)
Illumina Laboratory Services, Illumina	RCV000677462	SCV000915136	pathogenic	Mucopolysaccharidosis type 6	2018-09-10	criteria provided, single submitter	clinical testing	The ARSB c.1197C>G (p.Phe399Leu) missense variant has been reported in five studies and is found in a total of seven individuals with mucopolysaccharidosis, type VI, including in one in a homozygous state and in six in a compound heterozygous state, including one sibling pair (Yang et al. 2001; Ching-Wan et al. 2004; Lin et al. 2008; But et al. 2011; Zheng et al. 2014). The p.Phe399Leu variant was also found in a heterozygous state in two unaffected parents (Ching-Wan et al. 2004). The p.Phe399Leu variant was absent from 150 control subjects and is reported at a frequency of 0.000174 in the East Asian population of the Genome Aggregation Database. Based on the evidence, the p.Phe399Leu variant is classified as pathogenic for mucopolysaccharidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000677462	SCV001221173	pathogenic	Mucopolysaccharidosis type 6	2024-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 399 of the ARSB protein (p.Phe399Leu). This variant is present in population databases (rs200793396, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 11802522, 18486607, 25190157). ClinVar contains an entry for this variant (Variation ID: 559688). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARSB protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000677462	SCV004206771	pathogenic	Mucopolysaccharidosis type 6	2024-03-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000677462	SCV005727207	pathogenic	Mucopolysaccharidosis type 6	2024-11-04	criteria provided, single submitter	clinical testing	Variant summary: ARSB c.1197C>G (p.Phe399Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251354 control chromosomes. c.1197C>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (Yang_2001, Lin_2008, Zheng_2014, He_2021, Fang_2022). These data indicate that the variant is very likely to be 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: 34813777, 33985463, 18486607, 11802522, 25190157). ClinVar contains an entry for this variant (Variation ID: 559688). Based on the evidence outlined above, the variant was classified as pathogenic.