ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.824T>C (p.Leu275Pro)

dbSNP: rs2143001162
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Total submissions: 4
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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 RCV001578522 SCV001547803 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter research Absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Labcorp Genetics (formerly Invitae), Labcorp RCV001578522 SCV002208089 pathogenic Mucopolysaccharidosis, MPS-IV-A 2022-05-27 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 275 of the GALNS protein (p.Leu275Pro). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALNS protein function. ClinVar contains an entry for this variant (Variation ID: 1048420). This missense change has been observed in individual(s) with mucopolysaccharidosis IVA (PMID: 32216080, 34387910). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003399148 SCV004122460 uncertain significance not specified 2023-10-04 criteria provided, single submitter clinical testing Variant summary: GALNS c.824T>C (p.Leu275Pro) 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 was absent in 249496 control chromosomes (gnomAD). c.824T>C has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (examples: Caciotti_2015 and Peretz_2020). These data indicate that the variant may 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: 25545067, 32216080, 34387910). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001578522 SCV005641482 likely pathogenic Mucopolysaccharidosis, MPS-IV-A 2024-02-19 criteria provided, single submitter clinical testing

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