ClinVar Miner

Submissions for variant NM_005476.7(GNE):c.1281G>A (p.Lys427=)

dbSNP: rs1554659670
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000532647 SCV000632643 uncertain significance GNE myopathy; Sialuria 2021-08-28 criteria provided, single submitter clinical testing This sequence change affects codon 458 of the GNE mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GNE protein. This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). 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: 460451). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Eurofins Ntd Llc (ga) RCV000597411 SCV000705775 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001805154 SCV002050731 uncertain significance not specified 2021-12-01 criteria provided, single submitter clinical testing Variant summary: GNE c.1374G>A (p.Lys458Lys) alters a conserved nucleotide located to the last nucleotide of exon 7, therefor it could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site, and two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251416 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1374G>A in individuals affected with Inclusion Body Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV002527742 SCV003631944 uncertain significance Inborn genetic diseases 2022-07-21 criteria provided, single submitter clinical testing Occurs in the last base pair of the exon Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV001829573 SCV002075651 uncertain significance GNE myopathy 2021-08-06 no assertion criteria provided clinical testing

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