Submissions for variant NM_000512.5(GALNS):c.860C>T (p.Ser287Leu)

gnomAD frequency: 0.00002  dbSNP: rs770053354

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255770	SCV000321698	pathogenic	not provided	2015-03-16	criteria provided, single submitter	clinical testing	The S287L missense variant has been reported previously in association with MPS IVA in a patient with a severe MPS IVA phenotype who was homozygous for the S287L variant (Bunge et al., 1997). Mapping of the S287L variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon et al., 2012). Furthermore, S287L is a non-conservative amino acid substitution, which occurs at a position that is highly conserved across species, and missense variants in nearby residues (F284V, N289D, N289S, G290R, G290S) have also been reported in the Human Gene Mutation Database in association with MPS IVA (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Therefore, we interpret S287L to be a pathogenic variant.
Invitae	RCV000701162	SCV000829946	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 287 of the GALNS protein (p.Ser287Leu). This variant is present in population databases (rs770053354, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IV type A (PMID: 9298823, 15235041, 16287098, 23876334, 25252036, 29731656). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265169). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255770	SCV001249834	pathogenic	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000701162	SCV001366701	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2018-11-14	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP2,PP3.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000701162	SCV001547809	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; 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)
Revvity Omics, Revvity	RCV000701162	SCV002024156	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-06-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000701162	SCV002045010	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000701162	SCV002792927	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-03-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000701162	SCV004801250	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-03-14	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017572	SCV004848819	likely pathogenic	Morquio syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.Ser287Leu variant in GALNS has been reported in at least 2 homozygous and 2 compound heterozygous individuals with severe mucopolysaccharidosis IVa (Bunge 1997 PMID: 9298823, Tuysuz 2019 PMID: 30980944, Zanetti 2020 PMID: 32036093). It has also been reported in ClinVar (Variation ID 265169) and identified in 1/41450 African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Mapping of the variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon 2012 PMID: 22940367). In summary, this variant meets criteria to be classified as Likely pathogenic for autosomal recessive mucopolysaccharidosis IVa. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3, PS3_Supporting, PP4.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000701162	SCV001190762	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2020-02-05	no assertion criteria provided	clinical testing