Submissions for variant NM_000512.5(GALNS):c.611A>G (p.Asn204Ser)

dbSNP: rs569725936

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000431100	SCV000524914	likely pathogenic	not provided	2016-03-11	criteria provided, single submitter	clinical testing	The N204S variant in the GALNS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, other missense variants at this same codon (N204T and N204K), as well as missense variants in neighboring codons (A203V and G201E), have been reported in the Human Gene Mutation Database in association with MPS IVA (Stenson et al., 2014). Furthermore, N204 is one of two consensus N-linked oligosaccharide sites in the polypeptide sequence of GALNS (Dvorak-Ewell et al., 2010). The N204S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N204S variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The N204S variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae	RCV001861541	SCV002182876	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 204 of the GALNS protein (p.Asn204Ser). This variant is present in population databases (rs569725936, gnomAD 0.005%). This missense change has been observed in individual(s) with mucopolysaccharidosis IVA (PMID: 33256811). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 384194). 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%. This variant disrupts the p.Asn204 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1522213, 25252036). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV001861541	SCV002516436	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-05-04	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272233	SCV002556966	likely pathogenic	Skeletal dysplasia	2021-10-21	criteria provided, single submitter	clinical testing
Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital	RCV001861541	SCV004697577	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-01-01	criteria provided, single submitter	clinical testing