ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.1247T>C (p.Ile416Thr)

gnomAD frequency: 0.00093  dbSNP: rs142822371
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000331371 SCV000399629 uncertain significance Morquio syndrome 2016-06-14 criteria provided, single submitter clinical testing The c.1247T>C (p.Ile416Thr) variant has been identified in a homozygous state in one individual diagnosed with mucopolysaccharidosis, type IVA (Morrone et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00175 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Ile416Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for mucopolysaccharidosis, type IV.
Labcorp Genetics (formerly Invitae), Labcorp RCV000894656 SCV001038655 likely benign Mucopolysaccharidosis, MPS-IV-A 2024-01-31 criteria provided, single submitter clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000894656 SCV001547940 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter curation In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting)
Genome-Nilou Lab RCV000894656 SCV002044937 likely benign Mucopolysaccharidosis, MPS-IV-A 2021-11-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235192 SCV003934590 uncertain significance not specified 2023-05-09 criteria provided, single submitter clinical testing Variant summary: GALNS c.1247T>C (p.Ile416Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 249798 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (0.00092 vs 0.002), allowing no conclusion about variant significance. c.1247T>C has been reported in the literature in a homozygous individual affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Morrone_2014). These data indicate that the variant could be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24726177, 29140481). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments classifying the variant as uncertain significance (n=2) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV003480600 SCV004224273 uncertain significance not provided 2023-02-07 criteria provided, single submitter clinical testing

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