ClinVar Miner

Submissions for variant NM_000434.4(NEU1):c.544A>G (p.Ser182Gly) (rs398123392)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492831 SCV000583122 likely pathogenic not provided 2017-05-23 criteria provided, single submitter clinical testing The S182G variant in the NEU1 gene has been reported previously in the homozygous state in an individual with sialidosis type 1, diagnosed at 24 years old. The individual had myoclonus, mild dysphagia, normal leukocyte sialidase and oligosaccharide pattern, but decreased sialidase activity in fibroblasts (Lukong et al., 2000). The S182G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S182G 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 conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S182G as a likely pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781657 SCV000919869 pathogenic Sialidosis 2018-09-26 criteria provided, single submitter clinical testing Variant summary: NEU1 c.544A>G (p.Ser182Gly) results in a non-conservative amino acid change located in the Sialidase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 241352 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in NEU1 causing Sialidosis (9.5e-05 vs 0.0011), allowing no conclusion about variant significance. c.544A>G has been reported in the literature in multiple individuals affected with Sialidosis (Chen_2006, Lukong_2000). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Chen_2006, Lukong_2000). The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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