ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.776G>A (p.Arg259Gln)

gnomAD frequency: 0.00002  dbSNP: rs118204442
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000000741 SCV001547798 likely pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter curation 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)
Labcorp Genetics (formerly Invitae), Labcorp RCV000000741 SCV004297070 pathogenic Mucopolysaccharidosis, MPS-IV-A 2023-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 259 of the GALNS protein (p.Arg259Gln). This variant is present in population databases (rs118204442, gnomAD 0.04%). This missense change has been observed in individuals with mucopolysaccharidosis type IVA (PMID: 9298823, 24389823). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 706). 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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000000741 SCV004806111 pathogenic Mucopolysaccharidosis, MPS-IV-A 2024-03-25 criteria provided, single submitter clinical testing
GeneDx RCV004777560 SCV005389497 pathogenic not provided 2024-05-01 criteria provided, single submitter clinical testing Published functional studies found this variant is associated with significantly reduced enzyme activity and protein expression (PMID: 10814710); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25287660, 25501214, 23876334, 23657977, 9298823, 24726177, 29275451, 24389823, 9660054, 10814710, 32183856, 31980526, 22940367)
Fulgent Genetics, Fulgent Genetics RCV000000741 SCV005641483 pathogenic Mucopolysaccharidosis, MPS-IV-A 2024-06-06 criteria provided, single submitter clinical testing
OMIM RCV000000741 SCV000020891 pathogenic Mucopolysaccharidosis, MPS-IV-A 1998-05-01 no assertion criteria provided literature only
GeneReviews RCV000000741 SCV001761896 not provided Mucopolysaccharidosis, MPS-IV-A no assertion provided literature only

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