Submissions for variant NM_005476.7(GNE):c.598A>T (p.Ile200Phe)

gnomAD frequency: 0.00004  dbSNP: rs369328625

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674921	SCV000800337	uncertain significance	GNE myopathy	2018-06-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001318626	SCV001509338	uncertain significance	GNE myopathy; Sialuria	2024-11-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 231 of the GNE protein (p.Ile231Phe). This variant is present in population databases (rs369328625, gnomAD 0.01%). This missense change has been observed in individuals with inclusion body myopathy (PMID: 12497639, 24695763, 29305133). This variant is also known as Ile200Phe. ClinVar contains an entry for this variant (Variation ID: 558623). 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. Experimental studies have shown that this missense change does not substantially affect GNE function (PMID: 16503651). 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.
Revvity Omics, Revvity	RCV001784298	SCV002018491	likely pathogenic	not provided	2019-06-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005004355	SCV002785353	likely pathogenic	GNE myopathy; Sialuria; Thrombocytopenia 12 with or without myopathy	2024-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117482	SCV003800859	uncertain significance	not specified	2024-05-29	criteria provided, single submitter	clinical testing	Variant summary: GNE c.691A>T (p.Ile231Phe), also referred to as p.Ile200Phe in the literature, results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251334 control chromosomes. c.691A>T has been reported in the literature in the compound heterozygous state in at least two individuals affected with Inclusion Body Myopathy (e.g. Eisenberg_2003, Chaouch_2014, Pogoryelova_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed little to no damaging effect of this variant on UDP-GlcNAc 2-epimerase activity compared to the wild type protein (Penner_2006). The following publications have been ascertained in the context of this evaluation (PMID: 12497639, 24695763, 29305133, 16503651). ClinVar contains an entry for this variant (Variation ID: 558623). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001784298	SCV004032850	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	GNE: PM3:Very Strong, PM2:Supporting
GeneDx	RCV001784298	SCV005325861	uncertain significance	not provided	2023-10-25	criteria provided, single submitter	clinical testing	Reported in the compound heterozygous state with other variants in the GNE gene in two unrelated patients with GNE myopathy in published literature (PMID: 24695763); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19917666, 24796702, 12497639, 16503651, 29305133, 24695763)