Submissions for variant NM_000512.5(GALNS):c.868G>A (p.Gly290Ser)

gnomAD frequency: 0.00001  dbSNP: rs975409254

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578530	SCV001547815	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	In vitro functional studies supportive of a damaging effect on the gene product (low in vitro enzymatic activity; PS3_supporting); 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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271645	SCV002555711	pathogenic	Morquio syndrome	2022-06-07	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.868G>A (p.Gly290Ser) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain 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 4.3e-06 in 231084 control chromosomes (gnomAD). c.868G>A has been reported in the literature in multiple compound heterozygous individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A), often with a severe phenotype (example Tomatsu_1997, Wang_2010, He_2013, Zanetti_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. When expressed in GALN-deficient fibroblasts, the G290S variant protein shows a nearly complete loss of activity, strongly suggesting it impairs enzyme function (Tomatsu_1997). In addition, other missense substitutions at this codon (G290R, G290D) have been reported in individuals affected with Mucopolysaccharidosis IVA in HGMD database, indicating this residue is critical for GALNS protein function. One research institute has submitted an assessment for this variant to ClinVar after 2014 and classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578530	SCV004297067	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-09-15	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1048428). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GALNS function (PMID: 9375852). 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. This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 20574428, 24035930). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 290 of the GALNS protein (p.Gly290Ser).