Submissions for variant NM_000512.5(GALNS):c.1474G>A (p.Ala492Thr)

dbSNP: rs760300454

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centogene AG - the Rare Disease Company	RCV000985198	SCV001426497	pathogenic	Mucopolysaccharidosis, MPS-IV-A		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000985198	SCV002044936	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000985198	SCV002311143	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-06-23	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 800974). This variant has been observed in individuals with clinical features of mucopolysaccaridosis type IVA (PMID: 24726177, 32860008). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces alanine with threonine at codon 492 of the GALNS protein (p.Ala492Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000985198	SCV004804741	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-03-17	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017767	SCV004848736	likely pathogenic	Morquio syndrome	2022-08-26	criteria provided, single submitter	clinical testing	The p.Ala492Thr in GALNS has been reported in 1 homozygous and 1 compound heterozygous invidivuals with mucopolysaccharidosis type 4A (MPS IVA, aka Morquio syndrome A) (Morrone 2014 PMID: 24726177, Bertoli-Avella 2021 PMID: 32860008), and was absent in large population databases. Measurement of GALNS activity from leukocytes or cultured fibroblasts from the homozygous patient above showed low to absent activity (Morrone 2014 PMID: 24726177). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for MPS IVA in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PS3, PP3.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000985198	SCV001133223	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2019-09-26	no assertion criteria provided	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000985198	SCV001547975	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	flagged submission	research	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)