Submissions for variant NM_000512.5(GALNS):c.911G>T (p.Gly304Val)

gnomAD frequency: 0.00001  dbSNP: rs758439379

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413811	SCV000492005	uncertain significance	not specified	2016-11-14	criteria provided, single submitter	clinical testing	The G304V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. the G304V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578589	SCV001547834	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)
Genome-Nilou Lab	RCV001578589	SCV002044986	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578589	SCV003023276	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 304 of the GALNS protein (p.Gly304Val). This variant is present in population databases (rs758439379, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis IVA (PMID: 34387910; Invitae). ClinVar contains an entry for this variant (Variation ID: 373413). 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 disrupts the p.Gly304 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been observed in individuals with GALNS-related conditions (PMID: 24120057), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.