ClinVar Miner

Submissions for variant NM_000512.4(GALNS):c.181C>T (p.Arg61Trp) (rs145798311)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000420201 SCV000521166 likely pathogenic not provided 2016-03-11 criteria provided, single submitter clinical testing The R61W variant in the GALNS gene has been reported previously in mucopolysaccharidosis type IVA (MPS IVA) in an affected individual who was compound heterozygous for the R61W variant and another pathogenic variant (Tomatsu et al., 2005). Structural analysis of the R61W variant described it as a solvent-exposed hydrophobic residue, which is expected to be associated with an attenuated phenotype (Rivera-Colon et al., 2012). The R61W variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R61W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (D60N, D60E, G66R) have been reported in the Human Gene Mutation Database in association with MPS IVA (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R61W variant is a strong candidate for a pathogenic variant.
Invitae RCV000633462 SCV000754691 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2017-12-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 61 of the GALNS protein (p.Arg61Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs145798311, ExAC 0.01%). This variant has been reported in combination with another GALNS variant in three individuals, including two siblings affected with mucopolysaccharidosis IVa (PMID: 16287098, 23876334). ClinVar contains an entry for this variant (Variation ID: 381663). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; 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.

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