ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.499T>G (p.Phe167Val) (rs148565559)

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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 RCV000322011 SCV000399652 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2017-04-27 criteria provided, single submitter clinical testing The GALNS c.499T>G (p.Phe167Val) missense variant has been reported in two studies in which it was identified in a compound heterozygous state in two patients (siblings) who were described as having an attenuated clinical phenotype of mucopolysaccharidosis, type IVa (Tomatsu et al. 2005; Montaño et al. 2007). The variant was found in two of 383 control alleles and is reported at a frequency of 0.00163 in the European American population of the Exome Sequencing Project. Functional studies using stable expression in CHO-K1 cell lines showed that the p.Phe167Val variant reduced enzyme activity (7.5% of wild type) and substrate affinity when compared to wild type GALNS (Montaño et al. 2007). In silico analysis revealed that the Phe167 residue is located near the active site on the surface of the GALNS protein and is predicted to change the secondary structure of the protein and affect substrate recognition and binding (Rivera-Colón et al. 2012; Olarte-Avellaneda et al. 2014; Tamarozzi et al. 2014). Based on the limited evidence, the p.Phe167Val variant is classified as a variant of unknown significance, but suspicious for pathogenicity for mucopolysaccharidosis, type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000322011 SCV001420538 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with valine at codon 167 of the GALNS protein (p.Phe167Val). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is present in population databases (rs148565559, ExAC 0.1%). This variant has been observed in several individuals affected with mucopolysaccharidosis IVA (PMID: 17876718). ClinVar contains an entry for this variant (Variation ID: 321204). Experimental studies have shown that this missense change produces a enzyme with decreased substrate affinity (PMID: 17876718). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280624 SCV001467853 likely pathogenic Morquio syndrome 2020-12-24 criteria provided, single submitter clinical testing Variant summary: GALNS c.499T>G (p.Phe167Val) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 251410 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (0.001 vs 0.002), allowing no conclusion about variant significance. c.499T>G has been reported in the literature in at least two individuals affected with an attenuated form of Mucopolysaccharidosis Type IVA (Morquio Syndrome A; e.g. Tomatsu_2005, Montano_2007). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant results in <10% of normal enzyme activity and reduced affinity for substrate (e.g. Montano_2007). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000322011 SCV001547721 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter curation In vitro functional studies supportive of a damaging effect on the gene product (low in vitro enzymatic activity; PS3_supporting); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)

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