Submissions for variant NM_000512.5(GALNS):c.938C>T (p.Thr313Met)

gnomAD frequency: 0.00002  dbSNP: rs894525161

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578324	SCV001547848	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)
Revvity Omics, Revvity	RCV001578324	SCV002025252	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-10-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578324	SCV003443643	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-05-09	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 313 of the GALNS protein (p.Thr313Met). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with Morquio syndrome type A (PMID: 23876334, 25252036, 32993725). ClinVar contains an entry for this variant (Variation ID: 1048222). 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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001578324	SCV003915845	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-04-13	criteria provided, single submitter	clinical testing	A Heterozygous missense variation in exon 9 of the GALNS gene that results in the amino acid substitution of Methionine for Threonine at codon 313 was detected. The observed variant c.938C>T (p.Thr313Met) has not been reported in the 1000 genomes and has a MAF of 0.0016% in gnomAD databases. The in silico prediction of the variant is disease causing by MutationTaster. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331131	SCV004039050	pathogenic	Morquio syndrome	2023-08-11	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.938C>T (p.Thr313Met) 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 1.6e-05 in 250640 control chromosomes (gnomAD). c.938C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (e.g. Dung_2013, Bidchol_2014, Moisan_2020, Zanetti_2021) . These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25252036, 23876334, 32993725, 34387910). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001578324	SCV004100660	pathogenic	Mucopolysaccharidosis, MPS-IV-A		criteria provided, single submitter	clinical testing	The missense variant p.T313M in GALNS (NM_000512.5) has been reported previously in multiple affected individuals (PMID: 23876334, 25252036, 32993725) The p.T313M variant is observed in 2/34,528 (0.0058%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.T313M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 313 of GALNS is conserved in all mammalian species. The nucleotide c.938 in GALNS is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001578324	SCV004242438	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.143T>G
Dr.Nikuei Genetic Center	RCV001578324	SCV005200347	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-07-10	criteria provided, single submitter	clinical testing