Submissions for variant NM_000512.5(GALNS):c.415G>A (p.Gly139Ser)

gnomAD frequency: 0.00004  dbSNP: rs146093755

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254865	SCV000321696	pathogenic	not provided	2015-11-27	criteria provided, single submitter	clinical testing	The G139S pathogenic variant in the GALNS gene has been reported previously in association with MPS IVA (Tomatsu et al., 1997; Rivera-Colon et al., 2012; Morrone et al., 2014; Olarte-Avellaneda et al., 2014). Functional studies found that G139S is associated with nearly complete loss of N-acetylgalactosamine-6-sulfate sulfatase activity (Tomatsu et al., 1997). The G139S variant was not observed at any significant frequency 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 G139S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G139S as a pathogenic variant.
Invitae	RCV000691262	SCV000819014	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 139 of the GALNS protein (p.Gly139Ser). This variant is present in population databases (rs146093755, gnomAD 0.003%). This missense change has been observed in individuals with mucopolysaccharidosis type IVa (PMID: 9375852, 15235041, 23227063, 23876334). ClinVar contains an entry for this variant (Variation ID: 265167). 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%. Experimental studies have shown that this missense change affects GALNS function (PMID: 9375852). This variant disrupts the p.Gly139 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been observed in individuals with GALNS-related conditions (PMID: 30980944), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000254865	SCV000854801	pathogenic	not provided	2017-11-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000254865	SCV001249835	pathogenic	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000691262	SCV001547681	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	In vitro and in vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; 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)
Genome-Nilou Lab	RCV000691262	SCV002045028	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000691262	SCV002507190	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230469	SCV003929034	pathogenic	Morquio syndrome	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.415G>A (p.Gly139Ser) results in a non-conservative amino acid change to a highly conserved residue in the Sulfatase, N-terminal (IPR000917) domain 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 251092 control chromosomes. c.415G>A has been reported in the literature in multiple individuals affected with severe Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Tomatsu_1997, Bidchol_2014, Dung_2013, Lee_2012), and some were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, resulting in <10% of normal enzymatic activity (Tomatsu_1997). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.