Submissions for variant NM_000512.5(GALNS):c.425A>G (p.His142Arg)

dbSNP: rs1288895691

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001349763	SCV001544123	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with arginine at codon 142 of the GALNS protein (p.His142Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 20574428). 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"). This variant disrupts the p.His142 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25545067, 29731656, 30094185). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001349763	SCV001547692	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	Located in a mutational hot spot and/or critical and well-established functional domain without benign variation (PM1_moderate); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
CeGaT Center for Human Genetics Tuebingen	RCV001531861	SCV001747170	pathogenic	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001349763	SCV002044962	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004770088	SCV005380713	uncertain significance	not specified	2024-08-09	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.425A>G (p.His142Arg) 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250976 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.425A>G has been reported in the literature in the compound heterozygous state in at least one individual affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (e.g. Wang_2010) and in patients with out a clear diagnosis of Mucopolysaccharidosis Type IVA or the presences of a second pathogenic allele (e.g. Moosa_2022, Chuang_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 1045365). Other variants affecting this codon have been reported (HGMD and ClinVar databases). Based on the evidence outlined above, the variant was classified as uncertain significance.