Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, |
RCV001578528 | SCV001547813 | likely pathogenic | Mucopolysaccharidosis, MPS-IV-A | 2021-02-01 | criteria provided, single submitter | curation | In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_supporting); located in a mutational hot spot and/or critical and well-established functional domain without benign variation (PM1_moderate); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) |
Labcorp Genetics |
RCV001578528 | SCV004297068 | pathogenic | Mucopolysaccharidosis, MPS-IV-A | 2023-05-19 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn289 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24726177). 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: 1048426). This missense change has been observed in individual(s) with mucopolysaccharidosis IVA (PMID: 20574428). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 289 of the GALNS protein (p.Asn289Ser). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003987849 | SCV004803940 | uncertain significance | not specified | 2024-01-29 | criteria provided, single submitter | clinical testing | Variant summary: GALNS c.866A>G (p.Asn289Ser) results in a conservative amino acid change located in the Sulfatase, N-terminal (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 233974 control chromosomes. c.866A>G has been reported in the literature at a homozygous state in one individual affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (example, Wang_2010). These data indicate that the variant may be associated with disease. Computational analysis based on X-ray crystallography of GALNS protein suggest Asn289 may be within the predicted active cavity and involved in enzymeligand interaction (Olarte-Avellaneda_2014, Rivera-Colon_2012). However, to our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25287660, 22940367, 20574428). ClinVar contains an entry for this variant (Variation ID: 1048426). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |