ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.452C>T (p.Pro151Leu)

gnomAD frequency: 0.00001  dbSNP: rs559063128
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV001093710 SCV001190352 likely pathogenic Mucopolysaccharidosis, MPS-IV-A criteria provided, single submitter clinical testing A homozygous missense variation in exon 5 of the GALNS gene that results in the amino acid substitution of Leucine for Proline at codon 151 was detected. The observed variant c.452C>T(p.Pro151Leu) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is damaging by LRT and MutationTaster2. The reference codon is conserved across species. The allele frequency of the variant is Æ’ = 0.0000279 in gnomAD Exomes. In summary, the variant meets our criteria to be classified as likely pathogenic.
Centogene AG - the Rare Disease Company RCV001093710 SCV001424423 pathogenic Mucopolysaccharidosis, MPS-IV-A criteria provided, single submitter clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV001093710 SCV001547701 pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter curation In vitro and in vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_strong); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Genome-Nilou Lab RCV001093710 SCV002045026 likely pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-11-07 criteria provided, single submitter clinical testing
3billion RCV001093710 SCV002058449 pathogenic Mucopolysaccharidosis, MPS-IV-A 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000873056, PMID:7633425, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000321205, PMID:7795586,23227063,27243974, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.971, 3CNET: 0.993, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000028, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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