ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.676T>C (p.Phe226Leu)

dbSNP: rs1375452799
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV001578574 SCV001547765 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter curation The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_moderate); very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004699331 SCV005205123 uncertain significance not specified 2024-06-06 criteria provided, single submitter clinical testing Variant summary: GALNS c.676T>C (p.Phe226Leu) results in a non-conservative amino acid change located in the sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251332 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.676T>C has been reported in the literature in two compound heterozygous individuals affected with mucopolysaccharidosis Type IVA (Morquio Syndrome A) with <10% of normal GALNS activity in leukocytes; however, in both individuals the variant was also presumed to be in cis with another variant (Cozma_2015). As a result, this report does not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type IVA (Morquio Syndrome A). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26147980). ClinVar contains an entry for this variant (Variation ID: 1048472). Based on the evidence outlined above, the variant was classified as uncertain significance.

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