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

gnomAD frequency: 0.00001  dbSNP: rs199638097

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000274769	SCV000331062	pathogenic	not provided	2015-12-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818831	SCV000959465	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 47 of the GALNS protein (p.Gly47Arg). This variant is present in population databases (rs199638097, gnomAD 0.006%). This missense change has been observed in individual(s) with MPS IVA (PMID: 9298823, 23876334, 29275451, 30023300; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 281018). 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.
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)
Genome-Nilou Lab	RCV000818831	SCV002045040	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000818831	SCV002507159	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-05-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000818831	SCV003825750	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-06-03	criteria provided, single submitter	clinical testing