ClinVar Miner

Submissions for variant NM_005476.7(GNE):c.1760T>C (p.Ile587Thr)

gnomAD frequency: 0.00002  dbSNP: rs748949603
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000591867 SCV000701266 pathogenic not provided 2016-06-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763618 SCV000894472 pathogenic GNE myopathy; Sialuria 2022-04-08 criteria provided, single submitter clinical testing
Invitae RCV000763618 SCV001209855 pathogenic GNE myopathy; Sialuria 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 618 of the GNE protein (p.Ile618Thr). This variant is present in population databases (rs748949603, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive myopathy (PMID: 12497639, 24695763, 26231298). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1811T>C (Ile587Thr). ClinVar contains an entry for this variant (Variation ID: 188882). 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: 16503651). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000591867 SCV001248055 pathogenic not provided 2023-02-01 criteria provided, single submitter clinical testing GNE: PM3:Strong, PM1, PM2, PP4:Moderate, PP2
Revvity Omics, Revvity Omics RCV000591867 SCV002024881 pathogenic not provided 2024-01-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000366480 SCV002511602 pathogenic GNE myopathy 2022-04-24 criteria provided, single submitter clinical testing Variant summary: GNE c.1853T>C (p.Ile618Thr) results in a non-conservative amino acid change located in the ATPase, nucleotide binding domain (IPR043129) 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 4e-06 in 251492 control chromosomes. c.1853T>C has been reported in the literature as a founder mutation of Roma origin in homozygous and compound heterozygous genotypes among individuals affected with Inclusion Body Myopathy 2 (example, Tasca_2012, Chaouch_2014, Chamova_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion RCV000366480 SCV003842032 pathogenic GNE myopathy 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000188882). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 12497639, 26231298). A different missense change at the same codon (p.Ile587Asn) has been reported to be associated with GNE related disorder (PMID: 24027297). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000366480 SCV004048194 pathogenic GNE myopathy criteria provided, single submitter clinical testing The GNE c.1853T>C p.Ile618Thr variant has been reported in homozygous state in individuals affected with Nonaka myopathy (Penner J. et al., 2006). Experimental studies have shown that the variant affects GNE protein function (Penner J. et al., 2006). This variant is reported with the allele frequency (0.000008121) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. This sequence change replaces Isoleucine with Threonine at codon 618 of the GNE protein (p.Ile618Thr). The Isoleucine residue is highly conserved and there is a small physicochemical difference between Isoleucine and Threonine. The variant is predicted to be deleterious by SIFT. For these reasons, this variant has been classified as Pathogenic
Counsyl RCV000366480 SCV000220508 pathogenic GNE myopathy 2018-12-03 no assertion criteria provided clinical testing
GeneReviews RCV000366480 SCV001364093 not provided GNE myopathy no assertion provided literature only
Natera, Inc. RCV000366480 SCV001458433 pathogenic GNE myopathy 2020-09-16 no assertion criteria provided clinical testing

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