Submissions for variant NM_005476.7(GNE):c.1675G>A (p.Gly559Arg)

gnomAD frequency: 0.00001  dbSNP: rs762009737

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000305422	SCV000342146	uncertain significance	not provided	2016-05-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000672432	SCV000797537	uncertain significance	GNE myopathy	2018-02-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004544	SCV001163612	likely pathogenic	GNE myopathy; Sialuria		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001004544	SCV002285238	pathogenic	GNE myopathy; Sialuria	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 590 of the GNE protein (p.Gly590Arg). This variant is present in population databases (rs762009737, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive GNE-related myopathy (PMID: 2402797, 14972325, 30390020). This variant is also known as p.Gly559Arg. ClinVar contains an entry for this variant (Variation ID: 288129). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222477	SCV002500326	uncertain significance	not specified	2022-03-11	criteria provided, single submitter	clinical testing	Variant summary: GNE c.1768G>A (p.Gly590Arg) results in a non-conservative amino acid change located in the ManNAc kinase domain (Cerrino_2015) of 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 2.4e-05 in 251484 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1768G>A has been reported in the literature in individuals affected with Inclusion Body Myopathy 2, in one case with a known pathogenic second variant (Cerino_2015), however in other cases without a second allele provided or a second allele with uncertain clinical impact (Huizing_2003, Cho_2014, Chen_2019). Additionally, the variant was reported in 3 family members in the homozygous state who all had severe autosomal recessive macrothrombocytopenia with no signs of myopathy (>age 20; Manchev_2014), suggesting the variant is benign in nature or associated with later onset of symptoms. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000672432	SCV005058978	likely pathogenic	GNE myopathy	2024-03-28	criteria provided, single submitter	clinical testing