Submissions for variant NM_000512.5(GALNS):c.181C>T (p.Arg61Trp)

gnomAD frequency: 0.00004  dbSNP: rs145798311

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420201	SCV000521166	likely pathogenic	not provided	2016-03-11	criteria provided, single submitter	clinical testing	The R61W variant in the GALNS gene has been reported previously in mucopolysaccharidosis type IVA (MPS IVA) in an affected individual who was compound heterozygous for the R61W variant and another pathogenic variant (Tomatsu et al., 2005). Structural analysis of the R61W variant described it as a solvent-exposed hydrophobic residue, which is expected to be associated with an attenuated phenotype (Rivera-Colon et al., 2012). The R61W variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R61W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (D60N, D60E, G66R) have been reported in the Human Gene Mutation Database in association with MPS IVA (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R61W variant is a strong candidate for a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633462	SCV000754691	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 61 of the GALNS protein (p.Arg61Trp). This variant is present in population databases (rs145798311, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 23876334, 30797135; Invitae). ClinVar contains an entry for this variant (Variation ID: 381663). 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.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000633462	SCV001547611	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)
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000633462	SCV001960901	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-09-20	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 2 of the GALNS gene that results in the amino acid substitution of Tryptophan for Arginine at codon 61 was detected. The observed variant c.181C>T (p.Arg61Trp) has not been reported in the 1000 genomes and a minor allele frequency of 0.004% in the gnomAD databases. The in silico prediction of the variant is disease causing by DANN, SIFT and MutationTaster2. The variant has been classified as pathogenic by Uniprot and is present in the catalytic domain of the GALNS_HUMAN protein. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic variant.
Revvity Omics, Revvity	RCV000633462	SCV002025251	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-10-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000633462	SCV002045039	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics	RCV000633462	SCV002104177	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A		criteria provided, single submitter	research	The patients blood mRNA analysis demonstrated the alteration of splicing.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000633462	SCV002507153	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002230025	SCV002511530	likely pathogenic	Morquio syndrome	2022-04-05	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.181C>T (p.Arg61Trp) 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 4e-05 in 248128 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (4e-05 vs 0.002), allowing no conclusion about variant significance. c.181C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Tomatsu_2005, Dung_2013, Li_2019, Fang_2022). These data indicate that the variant is likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004742418	SCV005361882	likely pathogenic	GALNS-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The GALNS c.181C>T variant is predicted to result in the amino acid substitution p.Arg61Trp. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with autosomal recessive mucopolysaccharidosis IVA (see for example, Table 1, Dũng et al. 2013. PubMed ID: 23876334; Table S1, Yi et al. 2022. PubMed ID: 35212421; Table 2, Fang et al. 2022. PubMed ID: 34813777). This variant is documented in 0.016% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.