Submissions for variant NM_000512.5(GALNS):c.647T>C (p.Phe216Ser)

dbSNP: rs747805226

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001578571	SCV001547761	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_strong); 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	RCV001578571	SCV001960902	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-09-20	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 7 of the GALNS gene that results in the amino acid substitution of Serine for Phenylalanine at codon216 was detected. The observed variant c.647T>C (p.Phe216Ser) has not been reported in 1000 genomes and has a minor allele frequency of 0.0007% in the gnomAD databases. The in silico prediction of the variant is disease causing by DANN, SIFT and MutationTaster. The variant is in trans to a known pathogenic variant in the GALNS gene. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a likely pathogenic variant.
Genome-Nilou Lab	RCV001578571	SCV002045016	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578571	SCV002234455	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 216 of the GALNS protein (p.Phe216Ser). This variant is present in population databases (rs747805226, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 24726177, 25252036). ClinVar contains an entry for this variant (Variation ID: 1048469). 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. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001578571	SCV005073881	pathogenic	Mucopolysaccharidosis, MPS-IV-A		criteria provided, single submitter	clinical testing	The missense variant c.647T>C (p.Phe216Ser) in GALNS gene has been reported previously in homozygous and compound heterozygous states in multiple individuals with mucopolysaccharidosis IVA (Bidchol et al., 2014, Leong et al., 2019; Morrone et al., 2014). Experimental studies support a damaging effect on the gene product (low to null enzymatic activity) (Morrone et al., 2014). It is one of the most common mutation in Indian population (Bidchol et al., 2014). This variant is present with an allele frequency of 0.0008% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely pathogenic / 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 in GALNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Phe at position 216 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV001578571	SCV005904660	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-08-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001048469 /PMID: 24726177). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 24726177, 25252036). A different missense change at the same codon (p.Phe216Leu) has been reported to be associated with GALNS related disorder (ClinVar ID: VCV001470668). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005419099	SCV006085890	pathogenic	Morquio syndrome	2025-05-19	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.647T>C (p.Phe216Ser) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 8e-06 in 251314 control chromosomes. c.647T>C has been observed in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Morrone_2014, Bidchol_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 8% of normal activity in an in vitro assay (Morrone_2014). The following publications have been ascertained in the context of this evaluation (PMID: 25252036, 31200731, 24726177). ClinVar contains an entry for this variant (Variation ID: 1048469). Based on the evidence outlined above, the variant was classified as pathogenic.