ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.850T>G (p.Phe284Val) (rs144067930)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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, Partners HealthCare 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.; 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.
Invitae RCV000614681 SCV001387518 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with valine at codon 284 of the GALNS protein (p.Phe284Val). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is present in population databases (rs144067930, ExAC 0.06%). This variant has been observed in several individuals affected with mucopolysaccharidosis IV (PMID: 23876334, 30980944). ClinVar contains an entry for this variant (Variation ID: 321200). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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)

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