Submissions for variant NM_005476.7(GNE):c.32G>A (p.Arg11Gln)

gnomAD frequency: 0.00002  dbSNP: rs1401082365

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000732542	SCV000860510	uncertain significance	not provided	2018-04-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050314	SCV001214413	pathogenic	GNE myopathy; Sialuria	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 42 of the GNE protein (p.Arg42Gln). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with GNE-related myopathy (PMID: 32505938; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 596639). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg42 amino acid residue in GNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14972325, 16503651, 29480215). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004579561	SCV005062135	likely pathogenic	GNE myopathy	2024-03-22	criteria provided, single submitter	clinical testing	Variant summary: GNE c.125G>A (p.Arg42Gln) results in a conservative amino acid change in 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 4e-06 in 251378 control chromosomes (gnomAD). The variant, c.125G>A, has been reported in the literature in compound heterozygous individuals affected with Inclusion Body Myopathy 2 (e.g. Paul_2020, Zhang_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different missense change affecting the same amino acid (R42W) has been reported in several patients affected with GNE myopathy and is classified as (likely) pathogenic in ClinVar by multiple labs (Variation ID 550820). The following publications have been ascertained in the context of this evaluation (PMID: 32505938, 34676965). ClinVar contains an entry for this variant (Variation ID: 596639). Based on the evidence outlined above, the variant was classified as likely pathogenic.