ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs118203941
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) 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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Invitae RCV000179701 SCV001583438 pathogenic Mucopolysaccharidosis type 6 2021-12-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 405 of the ARSB protein (p.Cys405Tyr). This variant is present in population databases (rs118203941, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type VI (PMID: 1550123, 17458871; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 880). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000928 SCV000021078 pathogenic Mucopolysaccharidosis, type vi, severe 1992-04-01 no assertion criteria provided literature only

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