Submissions for variant NM_000512.5(GALNS):c.917T>G (p.Phe306Cys)

gnomAD frequency: 0.00002  dbSNP: rs759590432

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578317	SCV001547838	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_supporting); 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	RCV001578317	SCV004538762	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-08-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe306 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 34387910). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 1048214). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 34387910). This variant is present in population databases (rs759590432, gnomAD 0.008%). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 306 of the GALNS protein (p.Phe306Cys).