ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.139G>A (p.Gly47Arg) (rs199638097)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000274769 SCV000331062 pathogenic not provided 2015-12-03 criteria provided, single submitter clinical testing
Invitae RCV000818831 SCV000959465 likely pathogenic Mucopolysaccharidosis, MPS-IV-A 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 47 of the GALNS protein (p.Gly47Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs199638097, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with mucopolysaccharidosis type IVA (Invitae) and in several unrelated individuals as homozygous or in combination with another GALNS variant (PMID: 9298823, 23876334, 29275451). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 281018). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193130 SCV001361767 pathogenic Morquio syndrome 2019-04-05 criteria provided, single submitter clinical testing Variant summary: GALNS c.139G>A (p.Gly47Arg) 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 allele was found at a frequency of 1.6e-05 in 245094 control chromosomes (gnomAD and publications). c.139G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Bunge_1997, Pajares_GALNS_2012, Tomatsu_2004). The variant in its homozygous state appears to result in a severe phenotype (Bunge_1997, Tomatsu_2004). Yassaee et al (2017) also reported a patient carrying a different nucleotide change at the same position as the variant of interest (c.139G>C) causing the same amino acid change (p.G47R) in homozygous state. Biochemical analysis of lysosomal enzymes in this patient revealed no GALNS activity. These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000818831 SCV001547601 likely pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter research In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_moderate); 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)

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