Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Foundation for Research in Genetics and Endocrinology, |
RCV001062057 | SCV001190349 | likely pathogenic | Mucopolysaccharidosis, MPS-IV-A | criteria provided, single submitter | clinical testing | A Homozygous missense variation in exon 2 of the GALNS gene that results in the amino acid substitution of Arginine for Proline at codon 77 was detected. The observed variant c.230C>G (p.Pro77Arg) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is damaging by LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. | |
Labcorp Genetics |
RCV001062057 | SCV001226829 | pathogenic | Mucopolysaccharidosis, MPS-IV-A | 2022-10-26 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro77 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been observed in individuals with GALNS-related conditions (PMID: 25252036), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GALNS function (PMID: 10814710). 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: 856567). This missense change has been observed in individuals with mucopolysaccharidosis type IVA (MPS IVA) (PMID: 7633425, 15235041, 23876334; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 77 of the GALNS protein (p.Pro77Arg). |
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, |
RCV001062057 | SCV001547622 | likely pathogenic | Mucopolysaccharidosis, MPS-IV-A | 2021-02-01 | criteria provided, single submitter | curation | In vitro and 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_supporting); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) |
Genome- |
RCV001062057 | SCV002045038 | likely pathogenic | Mucopolysaccharidosis, MPS-IV-A | 2021-11-07 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV001062057 | SCV002792298 | likely pathogenic | Mucopolysaccharidosis, MPS-IV-A | 2022-03-17 | criteria provided, single submitter | clinical testing | |
Gene |
RCV003235459 | SCV003933621 | pathogenic | not provided | 2022-12-13 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22940367, 7633425, 25287660, 25501214, 30980944, 24726177, 15235041, 23876334, 32183856, 34387910, Sheth[article]2020) |
Neuberg Centre For Genomic Medicine, |
RCV001062057 | SCV004101537 | pathogenic | Mucopolysaccharidosis, MPS-IV-A | criteria provided, single submitter | clinical testing | The missense variant c.230C>G (p.Pro77Arg) in GALNS gene has been observed in several individuals affected with mucopolysaccharidosis type IV(Dung VC et.al.,2013). This variant has been reported to affect GALNS protein function (Sukegawa K et.al.,2000). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Pro77Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Pro at position 77 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. | |
Victorian Clinical Genetics Services, |
RCV001062057 | SCV005086936 | pathogenic | Mucopolysaccharidosis, MPS-IV-A | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis IVA (MIM#253000). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The phenotypic spectrum ranges from a severe and rapidly progressive early-onset form to a slowly progressive later-onset form (PMID: 23844448). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Two alternative amino acid changes at the same position have been observed in gnomAD (v2) (both 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sulfatase domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by multiple clinical diagnostic laboratories (ClinVar). In addition, it has been reported in multiple individuals with mucopolysaccharidosis IVA and has been suggested as a Gujarati-Indian founder variant (PMIDs: 15235041, 23876334, 24726177, 30980944, 35729508). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Leucocytes from patients homozygous for the p.(Pro77Arg) variant demonstrated severely reduced ß-galactose-6-sulfate sulfatase activity (PMID: 35729508). (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |