Submissions for variant NM_000512.5(GALNS):c.143T>G (p.Val48Gly)

dbSNP: rs191519947

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578362	SCV001547604	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	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	RCV001732134	SCV001983495	likely pathogenic	Morquio syndrome	2021-09-17	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.143T>G (p.Val48Gly) 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 4.8e-05 in 249368 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (4.8e-05 vs 0.002), allowing no conclusion about variant significance. c.143T>G has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) who had a second pathogenic variant and low GALNS activity, including a pair of siblings (Morrone_2014, Chin_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578362	SCV003259726	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 48 of the GALNS protein (p.Val48Gly). This variant is present in population databases (rs191519947, gnomAD 0.008%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 24726177, 32905071, 34387910). ClinVar contains an entry for this variant (Variation ID: 1048261). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001578362	SCV004242439	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-12-04	criteria provided, single submitter	clinical testing	Criteria applied: PM3_STR,PM2_SUP,PP3; Identified as compund heterozygous with NM_000512.5:c.938C>T