ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.1143-1G>C (rs431905495)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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)
Invitae RCV000000935 SCV001202468 pathogenic Mucopolysaccharidosis type 6 2019-11-20 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the ARSB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with mucopolysaccharidosis VI (PMID: 17458871). ClinVar contains an entry for this variant (Variation ID: 887). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 18406185). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ARSB are known to be pathogenic (PMID: 17458871, 22133300). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000935 SCV000021085 pathogenic Mucopolysaccharidosis type 6 2007-09-01 no assertion criteria provided literature only

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