ClinVar Miner

Submissions for variant NM_005476.7(GNE):c.1132G>T (p.Asp378Tyr) (rs199877522)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000484722 SCV000335272 pathogenic not provided 2015-09-11 criteria provided, single submitter clinical testing
GeneDx RCV000484722 SCV000565045 pathogenic not provided 2016-10-14 criteria provided, single submitter clinical testing The D409Y variant has been published (as D378Y using alternate nomenclature) as a recurrent pathogenic variant in individuals of European ancestry with autosomal recessive GNE-related myopathy (Nishino et al., 2002; Chaouch et al., 2014). Functional studies also showed that this variant reduced epimerase activity in vitro (Noguchi et al., 2004; Penner et al., 2006). The D409Y variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D409Y 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. Based on the currently available information, we interpret D409Y to be a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000596066 SCV000712454 pathogenic GNE myopathy 2016-08-25 criteria provided, single submitter clinical testing The p.Asp409Tyr variant in GNE has been reported in at least 12 compound heteroz ygous patients from 9 families (Chaouch 2014). In addition, this variant has bee n identified in 0.01% (14/121,022) of chromosomes by the Exome Aggregation Conso rtium (ExAC,; dbSNP rs199877522). Although this v ariant has been seen in the general population, its frequency is low enough to b e consistent with a carrier frequency. In vitro functional studies support an im pact to protein function (Noguchi 2004, Penner 2006). In summary, this variant m eets criteria to be classified as pathogenic for GNE-related myopathy based on g enetic and functional data.
Invitae RCV000707707 SCV000836816 pathogenic GNE myopathy; Sialuria 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 409 of the GNE protein (p.Asp409Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs199877522, ExAC 0.02%). This variant has been reported in combination with other GNE variants in several individuals affected with autosomal recessive GNE-related myopathy and is considered to be a recurrent pathogenic variant in individuals of European ancestry (PMID: 24695763, 12473753, 12497639). This variant is also known as p.D378Y in the literature. ClinVar contains an entry for this variant (Variation ID: 283278). Experimental studies have shown that this missense change results in the reduction of epimerase activity and kinase activity (PMID: 16503651, 14707127). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000596066 SCV000915287 pathogenic GNE myopathy 2018-10-09 criteria provided, single submitter clinical testing Variants in the GNE gene are known to cause GNE-related myopathies. The GNE c.1132G>T (p.Asp378Tyr) missense variant has been reported in at least three studies in which it is found in a compound heterozygous state in a total of five individuals with GNE-related myopathy (two of whom were related) (Eisenberg et al. 2003; Nishino et al. 2002; Leoyklang et al. 2014). The p.Asp378Tyr variant was absent from 50 control subjects and is reported at a frequency of 0.000324 in the European (non-Finnish) population of the Genome Aggregation Database. In vitro studies showed that p.Asp378Tyr variant was associated with 60% reduction of epimerase and a 50% reduction of kinase activity compared to wild type (Penner et al., 2006). Based on the evidence, the p.Asp378Tyr variant is classified as pathogenic for GNE-related myopathies. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl RCV000596066 SCV000678035 pathogenic GNE myopathy 2019-06-10 no assertion criteria provided clinical testing

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