Submissions for variant NM_000512.5(GALNS):c.850T>G (p.Phe284Val)

gnomAD frequency: 0.00017  dbSNP: rs144067930

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000614681	SCV000399640	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2017-04-28	criteria provided, single submitter	clinical testing	The GALNS c.850T>G (p.Phe284Val) missense variant has been reported in three studies in which it is found in a total of three patients with mucopolysaccharidosis type IV, including in one in a homozygous state, in one in a compound heterozygous state with a deletion on the second allele, and in one in a heterozygous state (Yamada et al. 1998; Dung et al. 2013; Morrone et al. 2014). The p.Phe284Val variant was absent from 200 control chromosomes (Dung et al. 2013), and is reported at a frequency of 0.0008 in the total population of the 1000 Genomes Project. The Phe284 residue is highly conserved and is located in a hydrophobic core of the protein (Dung et al. 2013; Olarte-Avellaneda et al. 2014). Enzyme activity in the individual who was compound hetreozygous for the variant was demonstrated to be only 4% of wild type (Morrone et al. 2014). Based on the evidence, the p.Phe284Val variant is classified as likely pathogenic for mucopolysaccharidosis, type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844697	SCV000712089	likely pathogenic	Morquio syndrome	2016-05-09	criteria provided, single submitter	clinical testing	The p.Phe284Val variant in GALNS has been reported in four patients with mucopol ysaccharidosis type IVa (one compound heterozygote and two homozygotes) (Yamada 1998, Morrone 2014, Dung 2013). This variant has also been identified in 0.04% ( 28/75778) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs144067930). Although this variant has been seen in t he general population, its frequency is low enough to be consistent with a reces sive carrier frequency. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summa ry, although additional studies are required to fully establish its clinical sig nificance, the p.Phe284Val variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000614681	SCV001387518	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2025-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 284 of the GALNS protein (p.Phe284Val). This variant is present in population databases (rs144067930, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mucopolysaccharidosis IV (PMID: 23876334, 30980944). ClinVar contains an entry for this variant (Variation ID: 321200). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	RCV000614681	SCV001547806	uncertain significance	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_supporting); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_supporting); very low frequency in gnomAD v2.1.1 (PM2_moderate)
Genome-Nilou Lab	RCV000614681	SCV002044951	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000844697	SCV003922701	likely pathogenic	Morquio syndrome	2024-07-31	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.850T>G (p.Phe284Val) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 244338 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (0.00022 vs 0.002), allowing no conclusion about variant significance. c.850T>G has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) as a homozygous and compound heterozygous genotype (e.g. Yamada_1998, Dung_2013, and Tuysuz_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 23876334, 9521421, 30609409, 34405919, 30980944). ClinVar contains an entry for this variant (Variation ID: 321200). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV004719798	SCV005325866	uncertain significance	not provided	2024-03-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 25501214, 22940367, 25287660, 30609409, 30980944, 34387910, 23876334, 16287098, 34813777, 34405919, 24726177, 9521421)
Fulgent Genetics, Fulgent Genetics	RCV000614681	SCV005641481	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-05-04	criteria provided, single submitter	clinical testing