Submissions for variant NM_000046.5(ARSB):c.1143-1G>C

gnomAD frequency: 0.00002  dbSNP: rs431905495

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000000935	SCV000458381	pathogenic	Mucopolysaccharidosis type 6	2017-04-27	criteria provided, single submitter	clinical testing	The ARSB c.1143-1G>C variant occurs in a canonical splice site (acceptor) and is predicted to disrupt or distort the normal gene product. The c.1143-1G>C variant has been reported in four studies in which it is found in at least 14 individuals with mucopolysaccharidosis, type VI, including one who carried the variant in a homozygous state and 13, including two siblings, who carried the variant in a compound heterozygous state (Garrido et al. 2007; Karageorgos et al. 2007; Garrido et al. 2008; Giraldo et al. 2016). The clinical phenotypes of these patients ranged from intermediate to severe. The c.1143-1G>C variant was absent from 50 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Functional studies showed that the variant resulted in lower levels of protein compared to wildtype, a range of 1-23% enzyme activity compared to controls, was subject to nonsense-mediated decay, and did not fully correctly localize to the lysosome (Karageorgos et al. 2007; Garrido et al. 2008). Based on the potential impact of splice acceptor variants and the evidence from the literature, the c.1143-1G>C variant is classified as pathogenic for mucopolysaccharidosis, type VI. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000935	SCV000694147	pathogenic	Mucopolysaccharidosis type 6	2016-11-18	criteria provided, single submitter	clinical testing	Variant summary: The ARSB c.1143-1G>C variant substitutes a highly conserved nucleotide at the canonical splice acceptor site in intron 5. 4/5 splice prediction tools predict abrogation of the splice acceptor site. The prediction results are verified by a functional assay: RT-PCR on a patients fibroblasts showed skipping of exon 6 (Garrido_2007). Exon 6 is encodes a part of alkaline-phosphatase-like, core domain (InterPro), thus skipping of exon 6 is expected to form non-functional protein. This variant is absent in 121248 control chromosomes from the broad and large populations of ExAC. It is found in several patients with mucopolysaccharidosis type VI with consistent recessive genotypes including evidence of cosegregation with disease (Karageorgos_2007, Garrido_2007, and Garrido_2015). In addition, multiple clinical reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000000935	SCV000802958	pathogenic	Mucopolysaccharidosis type 6	2018-01-01	criteria provided, single submitter	curation	Splicing variant in canonical site (PVS1); In vitro functional studies supportive of a damaging effect on the gene product (demonstrated nonsense mediated RNA decay; PS3); Very low frequency in GnomAD (PM2); Reputable source identifies as pathogenic (PP5)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000935	SCV001202468	pathogenic	Mucopolysaccharidosis type 6	2023-09-15	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 of the ARSB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs431905495, gnomAD 0.1%). Disruption of this splice site has been observed in individuals with mucopolysaccharidosis VI (PMID: 17458871). ClinVar contains an entry for this variant (Variation ID: 887). Studies have shown that disruption of this splice site results in exon 6 skipping and introduces a premature termination codon (PMID: 18406185). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000000935	SCV002777086	pathogenic	Mucopolysaccharidosis type 6	2021-12-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000935	SCV004206782	pathogenic	Mucopolysaccharidosis type 6	2024-02-11	criteria provided, single submitter	clinical testing
OMIM	RCV000000935	SCV000021085	pathogenic	Mucopolysaccharidosis type 6	2007-09-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000000935	SCV002084969	pathogenic	Mucopolysaccharidosis type 6	2021-07-26	no assertion criteria provided	clinical testing