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

gnomAD frequency: 0.00021  dbSNP: rs199877522

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000484722	SCV000335272	pathogenic	not provided	2015-09-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000484722	SCV000565045	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (60% reduction in epimerase activity and 50% reduction in kinase activity as compared to wild type) (Penner et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29305133, 12497639, 24695763, 16503651, 14707127, 12473753, 29382405, 19917666, 30467490, 30609409, 31127727, 24796702, 19596068, 27829678, 25123033, 24027297, 20301439, 29997562, 28641925, 30564623, 12325084, 26968811)
Laboratory for Molecular Medicine, Mass General Brigham 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, http://exac.broadinstitute.org; 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707707	SCV000836816	pathogenic	GNE myopathy; Sialuria	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 409 of the GNE protein (p.Asp409Tyr). This variant is present in population databases (rs199877522, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive GNE-related myopathy (PMID: 12473753, 12497639, 24695763). It is commonly reported in individuals of European ancestry (PMID: 12473753, 12497639, 24695763). This variant is also known as p.D378Y. ClinVar contains an entry for this variant (Variation ID: 283278). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. Experimental studies have shown that this missense change affects GNE function (PMID: 14707127, 16503651). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, 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.
Myriad Genetics, Inc.	RCV000596066	SCV001193776	pathogenic	GNE myopathy	2019-12-26	criteria provided, single submitter	clinical testing	NM_001128227.2(GNE):c.1225G>T(D409Y) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 12473753, 24695763, 14707127 and 16503651. Classification of NM_001128227.2(GNE):c.1225G>T(D409Y) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Illumina Laboratory Services, Illumina	RCV001165685	SCV001327915	uncertain significance	Sialuria	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Revvity Omics, Revvity	RCV000484722	SCV002024870	pathogenic	not provided	2022-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000596066	SCV004813787	pathogenic	GNE myopathy	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: GNE c.1225G>T (p.Asp409Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251400 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.1225G>T has been reported in the literature in multiple individuals affected with Inclusion Body Myopathy 2 (Noguchi_2004, Pogoryelova_2019). 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 and this variant results in reduced enzyme activity (Noguchi_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 30842975). ClinVar contains an entry for this variant (Variation ID: 283278). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV004021128	SCV004877104	pathogenic	Inborn genetic diseases	2023-11-17	criteria provided, single submitter	clinical testing	The c.1225G>T (p.D409Y) alteration is located in coding exon 7 of the GNE gene. This alteration results from a G to T substitution at nucleotide position 1225, causing the aspartic acid (D) at amino acid position 409 to be replaced by a tyrosine (Y)._x000D_ _x000D_ Based on the available evidence, the GNE c.1225G>T (p.D409Y) alteration is classified as pathogenic for autosomal recessive Nonaka myopathy; however, its clinical significance for autosomal dominant sialuria is uncertain. Based on data from gnomAD, the T allele has an overall frequency of 0.016% (45/282778) total alleles studied. The highest observed frequency was 0.033% (42/129128) of European (non-Finnish) alleles. This variant has been described as a British founder mutation after being reported in compound heterozygous form in numerous individuals affected with clinical and pathological findings consistent with GNE-related myopathy (Chaouch, 2014; Carrillo, 2018; Soule, 2018). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
GeneReviews	RCV000596066	SCV001364091	not provided	GNE myopathy		no assertion provided	literature only
Natera, Inc.	RCV000596066	SCV001458435	pathogenic	GNE myopathy	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000707707	SCV001749435	not provided	GNE myopathy; Sialuria		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 07-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.