ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.935C>G (p.Thr312Ser) (rs118204446)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193737 SCV001362799 pathogenic Morquio syndrome 2019-12-11 criteria provided, single submitter clinical testing Variant summary: GALNS c.935C>G (p.Thr312Ser) results in a conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250636 control chromosomes (gnomAD). c.935C>G has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A)(Yamada_1998). Authors indicate the variant causes a mild phenotype. These data indicate that the variant is very likely to be associated with disease. Functional analysis performed by Yamada_1998 found the variant to produce 15% normal activity. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000000748 SCV001547846 likely pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter research In vivo and in vitro 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_moderate); 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)
Invitae RCV000000748 SCV001591347 pathogenic Mucopolysaccharidosis, MPS-IV-A 2020-09-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 312 of the GALNS protein (p.Thr312Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs118204446, ExAC 0.002%). This variant has been observed in individual(s) with MPS IVA (PMID: 9521421, 15235041). ClinVar contains an entry for this variant (Variation ID: 713). 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. Experimental studies have shown that this variant affects GALNS protein function (PMID: 9521421, 10814710). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000748 SCV000020898 pathogenic Mucopolysaccharidosis, MPS-IV-A 1998-01-01 no assertion criteria provided literature only
GeneReviews RCV000000748 SCV000086809 pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-06-14 no assertion criteria provided literature only

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