ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.1019G>A (p.Gly340Asp)

dbSNP: rs267606838
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centogene AG - the Rare Disease Company RCV000000750 SCV001426611 pathogenic Mucopolysaccharidosis, MPS-IV-A criteria provided, single submitter clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000000750 SCV001547876 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_strong);the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Labcorp Genetics (formerly Invitae), Labcorp RCV000000750 SCV001591345 pathogenic Mucopolysaccharidosis, MPS-IV-A 2023-11-01 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 340 of the GALNS protein (p.Gly340Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 15235041, 20574428, 30458289, 30980944). ClinVar contains an entry for this variant (Variation ID: 18403). 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%. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000000750 SCV001984834 likely pathogenic Mucopolysaccharidosis, MPS-IV-A 2020-07-28 criteria provided, single submitter clinical testing This variant has been previously reported as a compound heterozygous and homozygous change in patients with Mucopolysaccharidosis IVA (PMID: 20574428, 15235041, 30980944, 30458289). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1019G>A (p.Gly340Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1019G>A (p.Gly340Asp) variant is classified as Likely Pathogenic.
Genome-Nilou Lab RCV000000750 SCV002045002 likely pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-11-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155036 SCV003844258 pathogenic Morquio syndrome 2023-02-27 criteria provided, single submitter clinical testing Variant summary: GALNS c.1019G>A (p.Gly340Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 192834 control chromosomes. c.1019G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Tomatsu_2004, Wang_2010, Cozma_2015), and some are 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 quantification of GALNS enzymatic product using blood samples from MPS IVA affected patients and normal controls, finding that samples from patients homozygous with the variant showed a nearly complete loss of activity (Cozma_2015). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000750 SCV000020900 pathogenic Mucopolysaccharidosis, MPS-IV-A 2010-08-01 no assertion criteria provided literature only

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