ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.498C>G (p.His166Gln)

dbSNP: rs1301198698
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centogene AG - the Rare Disease Company RCV001250221 SCV001424424 pathogenic Mucopolysaccharidosis, MPS-IV-A criteria provided, single submitter clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV001250221 SCV001547720 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter curation In vitro functional studies supportive of a damaging effect on the gene product (low in vitro enzymatic activity; PS3_supporting); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Genome-Nilou Lab RCV001250221 SCV002044960 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2021-11-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003387984 SCV004099640 pathogenic Morquio syndrome 2023-09-08 criteria provided, single submitter clinical testing Variant summary: GALNS c.498C>G (p.His166Gln) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). c.498C>G has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (examples: Tomatsu_1997, Tomatsu_2004, Bhattacharya_2014, and Cheema_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the variant caused severely reduced enzyme activity in transiently transfected fibroblast cells as compared with fibroblasts transfected with normal cDNA (Tomatsu_1997). The following publications have been ascertained in the context of this evaluation (PMID: 25433535, 33083013, 9375852, 15235041). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

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