Submissions for variant NM_000046.5(ARSB):c.1214G>A (p.Cys405Tyr) (rs118203941)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000723435	SCV000231992	pathogenic	not provided	2015-02-12	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova	RCV000179701	SCV000802975	uncertain significance	Mucopolysaccharidosis type 6	2018-01-01	criteria provided, single submitter	curation	Absent from GnomAD (PM2)
Integrated Genetics/Laboratory Corporation of America	RCV000779751	SCV000916526	pathogenic	Metachromatic leukodystrophy	2018-05-24	criteria provided, single submitter	clinical testing	Variant summary: ARSB c.1214G>A (p.Cys405Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Though the variant is located at an exon-intron junction, 5/5 computational tools predict no significant impact on normal splicing. These predictions have been confirmed by functional studies, where full-length mRNA containing the mutation c.1214G>A was detected (Jin 1992, Karageorgos 2007), predicted to result in a protein with the missense change p.C405Y. 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 246184 control chromosomes. This frequency is lower than expected for a pathogenic variant in ARSB causing Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (2e-05 vs 0.0022), allowing no conclusion about variant significance. The variant, c.1214G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) presenting with a slowly progressing, milder disease phenotype (Jin 1992, Karageorgos 2007). These data indicate that the variant is likely to be associated with disease. These publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Jin 1992, Karageorgos 2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000000928	SCV000021078	pathogenic	Mucopolysaccharidosis, type vi, severe	1992-04-01	no assertion criteria provided	literature only

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