Submissions for variant NM_000512.5(GALNS):c.245C>T (p.Ser82Leu)

gnomAD frequency: 0.00002  dbSNP: rs371429653

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079033	SCV000110902	uncertain significance	not provided	2015-01-05	criteria provided, single submitter	clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV001352891	SCV001547500	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-03-19	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001352891	SCV001547633	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Genome-Nilou Lab	RCV001352891	SCV002044969	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001352891	SCV002235973	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 82 of the GALNS protein (p.Ser82Leu). This variant is present in population databases (rs371429653, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 20574428, 23876334). ClinVar contains an entry for this variant (Variation ID: 93175). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271402	SCV002555605	likely pathogenic	Morquio syndrome	2022-06-03	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.245C>T (p.Ser82Leu) 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. 4/4 computational tools predict no significant impact on normal splicing, however, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 242556 control chromosomes (gnomAD). c.245C>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A, e.g. Wang_2010, Dung_2013, Bidchol_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as VUS, two as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001352891	SCV004801261	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-03-14	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV001352891	SCV005690597	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A		criteria provided, single submitter	clinical testing	The missense c.245C>T(p.Ser82Leu) variant, lying in splice region of GALNS gene has been reported previously in compound heterozygous and homozygous states in multiple individuals affected with Mucopolysaccharidosis IVA (Dũng VC, et. al., 2013; Zanetti et. al., 2021; Stranneheim et. al., 2021). This p.Ser82Leu variant is present with an allele frequency of 0.001% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic / Likely pathogenic. Multiple lines of computational evidence (Polyphen - Probably Damaging , SIFT - Damaging and MutationTaster - Disease causing) predict damaging effect on protein structure and function for this variant. The reference amino acid at this position on GALNS gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 82 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. However, functional studies are required to prove the pathogenicity of this variant conclusively. For these reasons, this variant has been classified as Likely Pathogenic.