ClinVar Miner

Submissions for variant NM_000434.4(NEU1):c.679G>A (p.Gly227Arg) (rs769765227)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494284 SCV000583127 pathogenic not provided 2017-07-31 criteria provided, single submitter clinical testing The G227R variant in the NEU1 gene has been reported previously in the homozygous and compound heterozygous state in several unrelated individuals with NEU1-related disorders (Lukong et al., 2000; Canafoglia et al., 2014; Schene et al., 2016; Muona et al., 2015). Functional analysis of G227R found that it is associated with significantly reduced enzymatic activity and lacks normal processing or lysosomal targeting (Lukong et al., 2000). The G227R 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 G227R 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 summary, G227R is interpreted to be a pathogenic variant
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587143 SCV000696697 pathogenic Sialidosis 2016-03-21 criteria provided, single submitter clinical testing Variant summary: The NEU1 c.679G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Arg. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Functional studies show that G227R has a sialidase activity of <10% of normal, and lacks normal processing and lysosomal targeting (Lukong_Hum. Mol. Genet._2000). This variant was found in 5/120902 control chromosomes at a frequency of 0.0000414, which does not significantly exceed maximal expected frequency of a pathogenic NEU1 allele (0.001118). The variant has been identified in homozygous state in patients with Sialidosis type II and in compound heterozygous state in patients with progressive myoclonus epilepsies or late-onset action myoclonus. Taken together, this variant was classified as pathogenic.
Invitae RCV000494284 SCV001421404 pathogenic not provided 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 227 of the NEU1 protein (p.Gly227Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs769765227, ExAC 0.009%). This variant has been observed in the homozygous state or in combination with another NEU1 variant in individuals with sialidosis and has been observed to segregate with sialidosis in families (PMID: 10767332, 19568825, 30023283, 24808020, 26141460). ClinVar contains an entry for this variant (Variation ID: 430342). This variant has been reported to affect NEU1 protein function (PMID: 10767332). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000494284 SCV001502480 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing

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