rs146093755
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000512.5(GALNS):c.415G>A(p.Gly139Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G139D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000512.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALNS | NM_000512.5 | c.415G>A | p.Gly139Ser | missense_variant | 4/14 | ENST00000268695.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALNS | ENST00000268695.10 | c.415G>A | p.Gly139Ser | missense_variant | 4/14 | 1 | NM_000512.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251092Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135870
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460640Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726642
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-IV-A Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Feb 01, 2021 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | May 09, 2022 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 10, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2015 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2016 | - - |
Morquio syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 04, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at