ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.901G>T (p.Gly301Cys) (rs118204443)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790840 SCV000232973 pathogenic not provided 2016-04-20 criteria provided, single submitter clinical testing
Invitae RCV000000743 SCV000825222 pathogenic Mucopolysaccharidosis, MPS-IV-A 2020-03-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 301 of the GALNS protein (p.Gly301Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs118204443, ExAC 0.03%). This variant is a common cause of mucopolysaccharidosis IVA in Colombia and it has been observed in homozygosis in several individuals affected with this disease (PMID: 9385378, 9298823, 15235041, 23876334). ClinVar contains an entry for this variant (Variation ID: 708). Experimental studies have shown that this missense change abrogates GALNS enzymatic activity (PMID: 10814710, 17876718). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000000743 SCV000894088 pathogenic Mucopolysaccharidosis, MPS-IV-A 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781400 SCV000919397 pathogenic Morquio syndrome 2018-04-24 criteria provided, single submitter clinical testing Variant summary: GALNS c.901G>T (p.Gly301Cys) 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 0.00011 in 111042 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (0.00011 vs 0.002), allowing no conclusion about variant significance. The variant, c.901G>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (e.g. Kato 1997, Bunge 1997, Dung 2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kato 1997). 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 RCV000000743 SCV001547832 pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter research In vitro and in 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_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)
OMIM RCV000000743 SCV000020893 pathogenic Mucopolysaccharidosis, MPS-IV-A 1997-11-01 no assertion criteria provided literature only

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