Submissions for variant NM_005476.7(GNE):c.2086G>T (p.Val696Leu)

dbSNP: rs121908627

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000430334	SCV000225561	uncertain significance	not provided	2016-12-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000430334	SCV000321743	uncertain significance	not provided	2022-04-11	criteria provided, single submitter	clinical testing	Reported as likely non-disease causing variant as it was identified in control populations and in silico analysis predicted the variant had nondamaging/mildly severe effect on GNE protein (Celeste et al., 2014); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30564623, 24796702, 28468868, 32759194)
Illumina Laboratory Services, Illumina	RCV000277092	SCV000480086	likely benign	GNE myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000315879	SCV000480087	likely benign	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000372863	SCV000480088	likely benign	Inclusion Body Myopathy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000430334	SCV000511635	uncertain significance	not provided	2016-11-08	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545813	SCV000632650	uncertain significance	GNE myopathy; Sialuria	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 727 of the GNE protein (p.Val727Leu). This variant is present in population databases (rs121908627, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with GNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 194025). Invitae Evidence 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 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. This variant disrupts the p.Val727 amino acid residue in GNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11528398, 12497639, 20175955, 21708040, 24005727, 25182749). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000430334	SCV000693291	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	GNE: PM5
Mayo Clinic Laboratories, Mayo Clinic	RCV000430334	SCV002540993	uncertain significance	not provided	2022-12-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000430334	SCV003815032	uncertain significance	not provided	2021-11-02	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000277092	SCV001457572	uncertain significance	GNE myopathy	2020-01-12	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000430334	SCV001963442	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000430334	SCV001968618	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003416070	SCV004109210	uncertain significance	GNE-related disorder	2024-05-22	no assertion criteria provided	clinical testing	The GNE c.2179G>T variant is predicted to result in the amino acid substitution p.Val727Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be an undocumented cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.