Submissions for variant NM_000512.5(GALNS):c.451C>A (p.Pro151Thr)

gnomAD frequency: 0.00001  dbSNP: rs781439830

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000374370	SCV000399653	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2017-04-27	criteria provided, single submitter	clinical testing	The GALNS c.451C>A (p.Pro151Thr) missense variant has been reported in two studies in which it is found in a total of six patients with mucopolysaccharidosis (MPS) type IV-A from four Korean families (Lee et al. 2012; Park et al. 2013). All six patients were compound heterozygous for the p.Pro151Thr variant and presented with a severe phenotype. Cho et al. (2014) report that the p.Pro151Thr variant is the most common variant in individuals from Korea with MPS type IV, accounting for 33% of disease-associated alleles. The p.Pro151Thr variant was absent from 50 controls and is reported at a frequency of 0.00012 in the East Asian population of the Exome Aggregation Consortium, but this is based on one allele only in a region of good sequence coverage, so the variant is presumed rare. Functional studies in patient leukocytes demonstrated a reduction in protein levels and GALNS activity to less than 20% of wildtype (Lee et al. 2012). Based on the evidence, the p.Pro151Thr variant is classified as pathogenic for mucopolysaccharidosis type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000374370	SCV001547700	likely pathogenic	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_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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000374370	SCV002231155	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-03-25	criteria provided, single submitter	clinical testing	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. This variant has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 23227063, 30458289). ‚ÄãClinVar contains an entry for this variant (Variation ID: 321205) This variant is present in population databases (rs781439830, ExAC 0.01%). This sequence change replaces proline with threonine at codon 151 of the GALNS protein (p.Pro151Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323515	SCV004028769	pathogenic	Morquio syndrome	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.451C>A (p.Pro151Thr) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251210 control chromosomes (gnomAD). c.451C>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (examples: Lee_2012, Uttarilli_2019, Lee_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23227063, 30408610, 35782601). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.