ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs747805226
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
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 observed missense variant c.647T>C(p.Phe216Ser) in GALNS gene has been reported previously in homozygous, compound heterozygous state in individuals with mucopolysaccharidosis IVA (Bidchol AM, et al., 2014, Leong HY, et al., 2019). The Phe216 is a buried non-polar residue and is substituted by charged/polar residues in the disease mutants and these mutations are expected to adversely introduce side chain mediated interactions, which in turn affect the local secondary structures as well as the hydrophobic core. It is one of the most common mutation in Indian population (Bidchol AM, et al., 2014). The c.647T>C variant has 0.001% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Phenyl alanine at position 216 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Phe216Ser in GALNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.