Submissions for variant NM_000512.5(GALNS):c.1157G>A (p.Arg386His)

gnomAD frequency: 0.00002  dbSNP: rs1221167717

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	RCV001578334	SCV001547908	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_moderate); 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	RCV002469379	SCV002766060	pathogenic	Morquio syndrome	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.1157G>A (p.Arg386His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249400 control chromosomes. c.1157G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (example, Tomatzu_2004, Pintos-Morell_2018, Tuysuz_2019, Moisan_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been ascertained in this evaluation. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578334	SCV004297061	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-09-09	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg386 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7795586, 9298823, 15309681, 22976768, 23227063, 24726177, 26147980). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1048232). This variant is also known as c.1158G>A (p.R386H). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 15309681). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 386 of the GALNS protein (p.Arg386His).