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

gnomAD frequency: 0.00001  dbSNP: rs398123392

Total submissions: 3

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000492831	SCV003439323	pathogenic	not provided	2023-07-25	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NEU1 protein function. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects NEU1 function (PMID: 10767332). ClinVar contains an entry for this variant (Variation ID: 430337). This missense change has been observed in individual(s) with sialidosis (PMID: 10767332, 29018767, 29414417, 30023283). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 182 of the NEU1 protein (p.Ser182Gly).